Imidazonaphthyridines

ABSTRACT

Imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds induce the biosynthesis of cytokines such as interferon and tumor necrosis factor. The compounds exhibit antiviral and antitumor properties. Methods of preparing the compounds and intermediates useful in the preparation of the compounds are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/004,674, filed Dec. 3, 2004, now U.S. Pat. No. 6,949,646, which is adivisional of U.S. application Ser. No. 10/824,232, filed Apr. 14, 2004,now U.S. Pat. No. 6,894,165, which is a divisional of U.S. applicationSer. No. 10/406,181, filed Apr. 3, 2003, now U.S. Pat. No. 6,797,716,which is a divisional of U.S. application Ser. No. 10/265,956, filedOct. 7, 2002, now U.S. Pat. No. 6,699,878, which is a divisional of U.S.application Ser. No. 09/706,990, filed Nov. 6, 2000, now U.S. Pat. No.6,514,985, which is a divisional of U.S. application Ser. No.09/210,114, filed Dec. 11, 1998, now U.S. Pat. No. 6,194,425, whichclaims the benefit of U.S. Provisional Application No. 60/069,276, filedDec. 11, 1997.

FIELD OF THE INVENTION

This invention relates to imidazonaphthyridine andtetrahydroimidazonaphthyridine compounds, processes for making thesecompounds and intermediates used in their preparation. This inventionadditionally relates to pharmaceutical compositions containingimidazonaphthyridine and tetrahydroimidazonaphthyridine compounds. Afurther aspect of this invention relates to the use of these compoundsas immunomodulators and for inducing cytokine biosynthesis in animals.

BACKGROUND OF THE INVENTION

The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system,Backman et al., J. Org. Chem. 15, 1278–1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87–92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537–1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. These are described in, interalia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986;5,268,376; 5,346,905; and 5,389,640, all of which are incorporatedherein by reference. Although there continues to be interest in theimidazoquinoline ring system, as seen for example in WO 98/30562, thereis a continuing need for compounds that have the ability to modulate theimmune response, by induction of cytokine biosynthesis or othermechanisms.

SUMMARY OF THE INVENTION

We have found a new class of compounds that are useful in inducingcytokine biosynthesis in animals. Accordingly, this invention providesimidazonaphthyridine compounds of Formula I:

wherein A, R₁ and R₂ are as defined hereinafter.

The invention also provides tetrahydroimidazonaphthyridine compounds ofFormula II:

wherein B, R₁ and R₂ are as defined hereinafter.

The compounds of Formula I and Formula II are useful as immune responsemodifiers due to their ability to induce cytokine biosynthesis andotherwise modulate the immune reponse when administered to animals. Thisability makes the compounds useful in the treatment of a variety ofconditions, e.g. viral diseases and tumors that are responsive to suchchanges in the immune response.

The invention further provides pharmaceutial compositions containing acompound of Formula I or Formula II and methods of inducing cytokinebiosynthesis in an animal and/or treating a viral infection in an animalby administering a compound of Formula I or Formula II to the animal.

In addition, methods of synthesizing compounds of Formula I and FormulaII, and intermediates useful in the synthesis of these compounds areprovided.

Further the invention provides a method of inducing interferonbiosynthesis in an animal comprising the step of administering to saidanimal a compound of Formula I or Formula II in an amount effective toinduce said interferon biosynthesis, and a method of treating a viralinfection in an animal comprising the step of administering to saidanimal a compound of Formula I or Formula II in an amount effective toinhibit the viral infection.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned earlier, the invention provides compounds of Formula I:

wherein

-   -   A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;    -   R₁ is selected from the group consisting of:    -   -hydrogen;    -   —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted or        substituted by one or more substituents selected from the group        consisting of:        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —O—C₁₋₂₀ alkyl,        -   —O—(C₁₋₂₀alkyl)₀₋₁-aryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;        -   —C₁₋₂₀alkoxycarbonyl;        -   —S(O)₀₋₂—C₁₋₂₀ alkyl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;        -   —N(R₃)₂;        -   —N₃;        -   oxo;        -   -halogen;        -   —NO₂;        -   —OH; and        -   —SH; and    -   —C₁₋₂₀ alkyl-NR₃—Q—X—R₄ or —C₂₋₂₀ alkenyl-NR₃—Q—X—R₄ wherein Q        is —CO— or —SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl;        heteroaryl; heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that        is unsubstituted or substituted by one or more substituents        selected from the group consisting of:        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —O—C₁₋₂₀ alkyl,        -   —O—(C₁₋₂₀alkyl)₀₋₁-aryl;        -   —O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;        -   —C₁₋₂₀ alkoxycarbonyl;        -   —S(O)₀₋₂—C₁₋₂₀ alkyl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;        -   —N(R₃)₂;        -   —NR₃—CO—O—C₁₋₂₀alkyl;        -   —N₃;        -   oxo;        -   -halogen;        -   —NO₂;        -   —OH; and        -   —SH; or R₄ is

-   -   -   wherein Y is —N— or —CR—;

-   R₂ is selected from the group consisting of:    -   -hydrogen;    -   —C₁₋₁₀ alkyl;    -   —C₂₋₁₀ alkenyl;    -   -aryl;    -   —C₁₋₁₀ alkyl —O—C₁₋₁₀-alkyl;    -   —C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and    -   —C₁₋₁₀ alkyl or C₂₋₁₀ alkenyl substituted by one or more        substituents selected from the group consisting of:        -   —OH;        -   -halogen;        -   —N(R₃)₂;        -   —CO—N(R₃)₂;        -   —CO—C₁₋₁₀ alkyl;        -   —N₃;        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —CO-aryl; and        -   —CO-heteroaryl;    -   each R₃ is independently selected from the group consisting of        hydrogen and C₁₋₁₀ alkyl; and    -   each R is independently selected from the group consisting of        hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and        trifluoromethyl, or a pharmaceutically acceptable salt thereof.

This invention also provides compounds of Formula II

wherein

-   -   B is —NR—C(R)₂—C(R)₂—C(R)₂—; —C(R)₂—NR—C(R)₂—C(R)₂—;        —C(R)₂—C(R)₂—NR—C(R)₂— or —C(R)₂—C(R)₂—C(R)₂—NR—;    -   R₁ is selected from the group consisting of:    -   -hydrogen;    -   —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted or        substituted by one or more substituents selected from the group        consisting of:        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —O—C₁₋₂₀alkyl;        -   —O—(C₁₋₂₀ alkyl)₀₋₁-aryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;        -   —C₁₋₂₀ alkoxycarbonyl;        -   —S(O)₀₋₂—C₁₋₂₀ alkyl;        -   —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;        -   —N(R₃)₂;        -   —N₃;        -   oxo;        -   -halogen;        -   —NO₂;        -   —OH; and        -   —SH; and    -   —C₁₋₂₀ alkyl-NR₃—Q—X—R₄ or —C₂₋₂₀ alkenyl-NR₃—Q—X—R₄ wherein Q        is —CO— or —SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl;        heteroaryl; heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that        is unsubstituted or substituted by one or more substituents        selected from the group consisting of:        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —O—C₁₋₂₀ alkyl,        -   —O—(C₁₋₂₀alkyl)₀₋₁-aryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;        -   —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;        -   —C₁₋₂₀ alkoxycarbonyl;        -   —S(O)₀₋₂—C₁₋₂₀ alkyl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;        -   —N(R₃)₂;        -   —NR₃—CO—O—C₁₋₂₀alkyl;        -   —N₃;        -   oxo;        -   -halogen;        -   —NO₂;        -   —OH; and        -   —SH; or R₄ is

-   -   -   wherein Y is —N— or —CR—;

-   R₂ is selected from the group consisting of:    -   -hydrogen;    -   —C₁₋₁₀ alkyl;    -   —C₂₋₁₀ alkenyl;    -   -aryl    -   —C₁₋₁₀alkyl —O—C₁₋₁₀-alkyl;    -   —C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and    -   —C₁₋₁₀ alkyl or C₂₋₁₀ alkenyl substituted by one or more        substituents selected from the group consisting of:        -   —OH;        -   -halogen;        -   —N(R₃)₂;        -   —CO—N(R₃)₂;        -   —CO—C₁₋₁₀ alkyl;        -   —N₃;        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   —CO-aryl; and        -   —CO-heteroaryl;    -   each R₃ is independently selected from the group consisting of        hydrogen and C₁₋₁₀ alkyl; and    -   each R is independently selected from the group consisting of        hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and        trifluoromethyl, or a pharmaceutically acceptable salt thereof.

As used herein, the terms “alkyl”, “alkenyl”, and the prefix “-alk” areinclusive of both straight chain and branched chain groups and of cyclicgroups, i.e. cycloalkyl and cycloalkenyl. These cyclic groups can bemonocyclic or polycyclic and preferably have from 3 to 10 ring carbonatoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl,cyclohexyl and adamantyl.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, tetrazolyl, imidazo, and so on.

“Heterocyclyl” includes non-aromatic rings or ring systems that containat least one ring hetero atom (e.g., O, S, N). Exemplary heterocyclicgroups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl,thiazolidinyl, and imidazolidinyl.

The aryl, heteroaryl and heterocyclyl groups may be unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of C₁₋₂₀ alkyl, hydroxy, halogen, N(R₃)₂, NO₂, C₁₋₂₀ alkoxy,C₁₋₂₀ alkylthio, trihalomethyl, C₁₋₂₀ acyl, arylcarbonyl,heteroarylcarbonyl, (C₁₋₁₀-alkyl)₀₋₁-aryl, (C₁₋₁₀alkyl)₀₋₁-heteroaryl,nitrile, C₁₋₂₀ alkoxycarbonyl, oxo, arylalkyl wherein the alkyl grouphas from 1 to 10 carbon atoms, and heteroarylalkyl wherein the alkylgroup has from 1 to 10 carbon atoms.

The invention is inclusive of the compounds described herein in any oftheir pharmaceutically acceptable forms, including isomers such asdiastereomers and enantiomers, salts, solvates, polymorphs, and thelike.

Preparation of the Compounds

Compounds of Formulas I and II wherein A is ═N—CR═CR—CR═ or B is—NR—C(R)₂—C(R)₂—C(R)₂— and R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme I:

Many 2-aminonicotinic acids of Formula III are known (see, for example,U.S. Pat. No. 3,917,624). The compound where R is hydrogen iscommercially available. In step (1) of Reaction Scheme I a2-aminonicotinic acid of Formula III is reacted with acetic anhydride byheating to provide a 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one ofFormula IV. The compound of Formula IV where R is hydrogen is known andits preparation has been disclosed in U.S. Pat. No. 3,314,941 (Littell),the disclosure of which is incorporated herein by reference.

In step (2) of Reaction Scheme I a compound of Formula IV is reactedwith sodium azide in a suitable solvent such as acetic acid to provide atetrazolyl nicotinic acid of Formula V. The reaction conveniently may berun at ambient conditions.

In step (3) of Reaction Scheme I an acid of Formula V is esterified toprovide a compound of Formula VI. The esterification may be carried outusing conventional methods. For example, the acid may be esterified inacetone using potassium carbonate and ethyl iodide.

In step (4) of Reaction Scheme I a compound of Formula VI is cyclized toprovide a tetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VII. Thereaction may be carried out by reacting the compound of Formula VI withan alkoxide in a suitable solvent, e.g., potassium ethoxide inN,N-dimethylformamide, at ambient conditions.

In step (5) of Reaction Scheme I a compound of Formula VII is nitratedusing a suitable nitrating agent such as nitric acid to provide a4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VIII.

In step (6) of Reaction Scheme I a compound of Formula VIII is convertedto a triflate of Formula IX. The reaction is preferably carried out bycombining a compound of Formula VIII with a base, preferably a tertiaryamine such as triethyl amine, in a suitable solvent such asdichloromethane and then adding trifluoromethanesulfonic anhydride. Theaddition is preferably carried out in a controlled manner, e.g., addingdropwise at a reduced temperature such as, for example, at about 0° C.The product can be isolated by conventional methods or it can be carriedon without isolation as described below in connection with step (7).

In step (7) of Reaction Scheme I a compound of Formula IX is reactedwith an amine of formula R₁NH₂ where R₁ is as defined above to provide a4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-amine of Formula X. Thereaction can be carried out by adding the amine to the reaction mixtureresulting from step (6). The reaction can also be carried out by addingthe amine to a solution of the compound of Formula IX and a tertiaryamine in a suitable solvent such as dichloromethane.

In step (8) of Reaction Scheme I a compound of Formula X is reduced toprovide a tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine of Formula XI.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon orpalladium on carbon. The reaction can conveniently be carried out on aParr apparatus in a suitable solvent such as ethanol.

In step (9) of Reaction Scheme I a compound of Formula XI is reactedwith a carboxylic acid or an equivalent thereof to provide a1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine of Formula XII.Suitable equivalents to carboxylic acid include acid halides,orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid orequivalent is selected such that it will provide the desired R₂substituent in a compound of Formula XII. For example,diethoxymethylacetate will provide a compound where R₂ is hydrogen andvaleryl chloride will provide a compound where R₂ is butyl. The reactioncan be run in the absence of solvent, in a carboxylic acid such asacetic acid, or in an inert solvent in the presence of a carboxylicacid. The reaction is run with sufficient heating to drive off anyalcohol or water formed as a byproduct of the reaction.

In step (10) of Reaction Scheme I a compound of Formula XII is reactedwith triphenylphosphine to provide aN-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine ofFormula XIII. The reaction can be carried out by combining a compound ofFormula XII with triphenylphosphine in a suitable solvent such as1,2-dichlorobenzene and heating.

In step (11) of Reaction Scheme I a compound of Formula XIII ishydrolyzed to provide a 1H-imidazo[4,5-c][1,8]naphthyridin-4-amine ofFormula XIV which is a subgenus of Formula I. The hydrolysis can becarried out by conventional methods such as by heating in a loweralkanol in the presence of an acid. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

In step (12) of Reaction Scheme I a compound of Formula XIV is reducedto provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of FormulaXV which is a subgenus of Formula II. The reduction is carried out bysuspending or dissolving a compound of Formula XIV in trifluoroaceticacid, adding a catalytic amount of platinum (IV)oxide, and thensubjecting the mixture to hydrogen pressure. The reaction can beconveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Alternatively, as illustrated in step (13) of Reaction Scheme I, a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of FormulaXV can be prepared by reduction of a compound of Formula XII. Thereduction is carried out by suspending or dissolving a compound ofFormula XII in trifluoroacetic acid, adding a catalytic amount ofplatinum (IV)oxide, and then subjecting the mixture to hydrogenpressure. The reaction can be conveniently carried out in a Parrapparatus. As above, the product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

Compounds of Formulas I and II wherein A is ═CR—N═CR—CR═ or B is—C(R)₂—NR—C(R)₂—C(R)₂—; R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme II.

In step (1) of Reaction Scheme II a 3-aminoisonicotinic acid of FormulaXVI is reacted with acetic anhydride by heating to provide a2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one of Formula XVII. The compoundof Formula XVII where R is hydrogen is known and its preparation hasbeen disclosed in Littell cited above.

In step (2) of Reaction Scheme II a compound of Formula XVII is reactedwith sodium azide in a suitable solvent such as acetic acid to provide atetrazolyl isonicotinic acid of Formula XVIII. The reaction convenientlymay be run at ambient conditions.

In step (3) of Reaction Scheme II an acid of Formula XVIII is esterifiedto provide a compound of Formula XIX. The esterification may be carriedout using conventional methods. For example, the acid may be esterifiedin acetone using potassium carbonate and ethyl iodide or by reactingwith dimethylformamide diethyl acetal in a suitable solvent such asdichloromethane.

In step (4) of Reaction Scheme II a compound of Formula XIX is cyclizedto provide a tetrazolo[1,5-a][1,7]naphthyridin-5-ol of Formula XX. Thereaction may be carried out by reacting the compound of Formula XIX withan alkoxide in a suitable solvent, e.g., potassium ethoxide inN,N-dimethylformamide, at ambient conditions.

In step (5) of Reaction Scheme II a compound of Formula XX ischlorinated using a suitable chlorinating agent such as thionylchloride, oxalyl chloride, phosphorus pentachloride or preferablyphosphorus oxychloride to provide a5-chlorotetrazolo[1,5-a][1,7]naphthyridine of Formula XXI. The reactioncan be carried out in an inert solvent or if appropriate in neatchlorinating agent. Preferred reaction conditions involve reaction inneat phosphorus oxychloride with heating at about 90° C.

In step (6) of Reaction Scheme II a compound of Formula XXI is reactedwith an amine of formula R₁NH₂ where R₁ is as defined above to provide atetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXII. The reactioncan be carried out by heating with an excess of the amine.

In step (7) of Reaction Scheme II a compound of Formula XXII is nitratedusing a suitable nitrating agent such as nitric acid to provide a4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXIII.Preferably the reaction is carried out in acetic acid with mild heatingand an excess of nitric acid.

In step (8) of Reaction Scheme II a compound of Formula XXIII is reducedto provide a tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine of FormulaXXIV. Preferably the reduction is carried out using an excess of sodiumhydrogensulfide in a suitable solvent such as acetic acid.

In step (9) of Reaction Scheme II a compound of Formula XXIV is reactedwith a carboxylic acid or an equivalent thereof to provide a1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine of Formula XXV.Suitable equivalents to carboxylic acid include acid halides,orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid orequivalent is selected such that it will provide the desired R₂substituent in a compound of Formula XXV. For example,diethoxymethylacetate will provide a compound where R₂ is hydrogen andvaleryl chloride will provide a compound where R₂ is butyl. The reactioncan be run in the absence of solvent, in a carboxylic acid such asacetic acid, or in an inert solvent in the presence of a carboxylicacid. The reaction is run with sufficient heating to drive off anyalcohol or water formed as a byproduct of the reaction.

In step (10) of Reaction Scheme II a compound of Formula XXV is reactedwith triphenylphosphine to provide aN-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine ofFormula XXVI. The reaction can be carried out by combining a compound ofFormula XXV with triphenylphosphine in a suitable solvent such as1,2-dichlorobenzene and heating.

In step (11) of Reaction Scheme II a compound of Formula XXVI ishydrolyzed to provide a 1H-imidazo[4,5-c][1,7]naphthyridin-4-amine ofFormula XXVII which is a subgenus of Formula I. The hydrolysis can becarried out by conventional methods such as by heating in a loweralkanol in the presence of an acid. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

In step (12) of Reaction Scheme II a compound of Formula XXVII isreduced to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of FormulaXXVIII which is a subgenus of Formula II. The reduction is carried outby suspending or dissolving a compound of Formula XXVII intrifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide,and then subjecting the mixture to hydrogen pressure. The reaction canbe conveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Alternatively, as illustrated in step (13) of Reaction Scheme II, a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of FormulaXXVIII can be prepared by reduction of a compound of Formula XXV. Thereduction is carried out by suspending or dissolving a compound ofFormula XXV in trifluoroacetic acid, adding a catalytic amount ofplatinum (IV)oxide, and then subjecting the mixture to hydrogenpressure. The reaction can be conveniently carried out in a Parrapparatus. The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

Compounds of Formulas I and II wherein A is ═CR—CR═CR—N═ or B is—C(R)₂—C(R)₂—C(R)₂—NR— and R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme III.

In step (1) of Reaction Scheme III a 3-nitro[1,5]naphthyridin-4-ol ofFormula XXIX is chlorinated using a suitable chlorinating agent such asphosphorus oxychloride to provide a 4-chloro-3-nitro[1,5]naphthyridineof Formula XXX. The reaction can be carried out by reacting a compoundof Formula XXIX with phosphorus oxychloride in a suitable solvent suchas N,N-dimethylformamide with mild heating (˜55° C.). The compound maybe isolated by conventional methods or it can be carried on withoutisolation as described below in connection with step (2). The compoundof Formula XXIX where R is hydrogen is known and its preparation hasbeen disclosed in Hart, Journal of the Chemical Society pp. 212–214,(1956).

In step (2) of Reaction Scheme III a 4-chloro-3-nitro[1,5]naphthyridineof Formula XXX is reacted with an amine of Formula R₁NH₂ where R₁ is asdefined above to provide a 3-nitro[1,5]naphthyridin-4-amine of FormulaXXXI. The reaction can be carried out by adding water then excess amineto the reaction mixture resulting from step (1) then heating on a steambath. The reaction can also be carried out by adding excess amine to asolution of a compound of Formula XXX in a suitable solvent such asdichloromethane and optionally heating. The compound of Formula XXXIwhere R₁ is hydrogen is known and its preparation has been disclosed inWozniak et al, J. R. Neth. Chem. Soc. 102 (12), pp. 511–13 (1983).

In step (3) of Reaction Scheme III a 3-nitro[1,5]naphthyridin-4-amine ofFormula XXXI is reduced to provide a [1,5]naphthyridine-3,4-diamine ofFormula XII. Preferably, the reduction is carried out using aconventional heterogeneous hydrogenation catalyst such as platinum oncarbon or palladium on carbon. The reaction can conveniently be carriedout on a Parr apparatus in a suitable solvent such as ethyl acetate.

In step (4) of Reaction Scheme III a compound of Formula XXXII isreacted with a carboxylic acid or an equivalent thereof to provide a1H-imidazo[4,5-c][1,5]naphthyridine of Formula XIII. Suitableequivalents to carboxylic acid include acid halides, orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XIII. For example, diethoxymethylacetate willprovide a compound where R₂ is hydrogen and trimethylorthovalerate willprovide a compound where R₂ is butyl. The reaction can be run in theabsence of solvent, in a carboxylic acid such as acetic acid, or in aninert solvent in the presence of an acid. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction.

Alternatively, step (4) may be carried out by (i) reacting a compound ofFormula XXXII with an acylating agent; and then (ii) cyclizing theproduct. Part (i) involves reacting a compound of Formula XXXII with anacyl halide of formula R₂C(O)X wherein R₂ is as defined above and X ischloro or bromo. The reaction can be carried out by adding the acylhalide in a controlled fashion (e.g. dropwise) to a solution of acompound of Formula XXXII in a suitable solvent such as dichloromethaneat a reduced temperature (e.g., 0° C.). The resulting amide intermediatecan be isolated by removal of the solvent. Part (ii) involves cyclizingthe product of part (i) by reacting it with methanolic ammonia at anelevated temperature (e.g. 150° C.) and pressure.

In step (5) of Reaction Scheme III a compound of Formula XXXIII isoxidized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide ofFormula XXXIV using a conventional oxidizing agent that is capable offorming N-oxides. Preferred reaction conditions involve reacting asolution of a compound of Formula XXXIII in chloroform with3-chloroperoxybenzoic acid at ambient conditions.

In step (6) of Reaction Scheme III a compound of Formula XXXIV isaminated to provide a 1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ofFormula XXXV which is a subgenus of Formula I. Step (6) involves (i)reacting a compound of formula XXXIV with an acylating agent; and then(ii) reacting the product with an aminating agent. Part (i) of step (6)involves reacting an N-oxide with an acylating agent. Suitable acylatingagents include alkyl- or arylsulfonyl chlorides (e.g., benzenesulfonylchloride, methanesulfonyl choride, p-toluenesulfonyl chloride).Arylsulfonyl chlorides are preferred. p-Toluenesulfonyl chloride is mostpreferred. Part (ii) of step (6) involves reacting the product of part(i) with an excess of an aminating agent. Suitable aminating agentsinclude ammonia (e.g., in the form of ammonium hydroxide) and ammoniumsalts (e.g., ammonium carbonate, ammonium bicarbonate, ammoniumphosphate). Ammonium hydroxide is preferred. The reaction is preferablycarried out by dissolving the N-oxide of Formula XXXIV in an inertsolvent such as dichloromethane, adding the aminating agent to thesolution, and then adding the acylating agent. Preferred conditionsinvolve cooling to about 0° C. to about 5° C. during the addition of theacylating agent. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

Alternatively step (6) may be carried out by (i) reacting a compound ofFormula XXXIV with an isocyanate; and then (ii) hydrolyzing the product.Part (i) involves reacting the N-oxide with an isocyanate wherein theisocyanato group is bonded to a carbonyl group. Preferred isocyanatesinclude trichloroacetyl isocyanate and aroyl isocyanates such as benzoylisocyanate. The reaction of the isocyanate with the N-oxide is carriedout under substantially anhydrous conditions by adding the isocyanate toa solution of the N-oxide in an inert solvent such as dichloromethane.The resulting product can be isolated by removal of the solvent. Part(ii) involves hydrolysis of the product from part (i). The reaction canbe carried out by conventional methods such as heating in the presenceof water or a lower alkanol optionally in the presence of a catalystsuch as an alkali metal hydroxide or lower alkoxide.

In step (7) of Reaction Scheme III a compound of Formula XXXV is reducedto provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine of FormulaXXXVI which is a subgenus of Formula II. The reduction is carried out bysuspending or dissolving a compound of Formula XXXV in trifluoroaceticacid, adding a catalytic amount of platinum (IV) oxide, and thensubjecting the mixture to hydrogen pressure. The reaction can beconveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Certain functional groups recited in connection with R₁ and R₂ may beincompatible with some of the reagents of Reaction Schemes I, II andIII. Compounds containing such functional groups can be prepared bythose skilled in the art using well known methods of functional groupprotection and manipulation. For example, amine groups may be protectedwhen necessary by derivatizing with di-tert-butyl dicarbonate.

Some compounds of Formula I or Formula II containing certain functionalgroups may be readily prepared from other compounds of Formula I orFormula II. For example, compounds wherein the R₁ substituent containsan amide group may conveniently be prepared by reacting an acid chloridewith a compound of Formula I or Formula II wherein the R₁ substituentcontains a primary amine. Likewise, compounds wherein the R₁ substituentcontains a urea group may be prepared by reacting an isocyanate with acompound of Formula I or Formula II wherein the R₁ substituent containsa primary amine. Further, compounds wherein the R₁ substituent containsa carbamate group may be prepared by reacting a chloroformate with acompound of Formula I or Formula II wherein the R₁ substituent containsa primary amine.

Certain of the intermediate compounds useful in the preparation ofcompounds of Formula I and Formula II have not been previouslydescribed. Therefore, the invention also provides intermediate compoundsuseful in the preparation of compounds of Formula I and Formula II. Thestructural formulas of these novel intermediates are set forth below.These compounds have the following structural formulas:

-   -   wherein R₁, R₂ and A are as defined above for compounds of        Formula I and Formula II.

-   -   wherein R, R₁, and R₂ are as defined above for compounds of        Formula I and Formula II.

-   -   wherein R, R₁ and R₂ are as defined above for compounds of        Formula I and Formula II.

-   -   wherein R₇ is OH, halogen or NHR₁ (and A and R₁ are as defined        above for compounds of Formula I) and R₈ is H, NO₂ or NH₂.

-   -   wherein A is as defined above for compounds of Formula I and R₉        is H or C₁₋₁₀ alkyl.

-   -   wherein R and R₁ are as defined above for compounds of Formula I        and Formula II with the proviso that R₁ is other than hydrogen,        and R₁₀ is NO₂ or NH₂.        Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound of Formula I or Formula II as definedabove in combination with a pharmaceutically acceptable carrier. As usedherein, the term “a therapeutically effective amount” means an amount ofthe compound sufficient to induce a therapeutic effect, such as cytokineinduction or antiviral activity. Although the exact amount of activecompound used in a pharmaceutical composition of the invention will varyaccording to factors known to those of skill in the art, such as thephysical and chemical nature of the compound as well as the nature ofthe carrier and the intended dosing regimen, it is anticipated that thecompositions of the invention will contain sufficient active ingredientto provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about10 μg/kg to about 5 mg/kg of the compound to the subject. Any of theconventional dosage forms may be used, such as tablets, lozenges,parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and so on.

The compounds of the invention have been shown to induce the productionof certain cytokines in experiments performed according to the TestMethod set forth below. This ability indicates that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

Cytokines that are induced by the administration of compounds accordingto the invention generally include interferon (IFN) and tumor necrosisfactor (TNF) as well as certain interleukins (IL). In particular, thecompounds induce IFN-α, TNF-α, IL-1,6, 10 and 12, and a variety of othercytokines. Among other effects, cytokines inhibit virus production andtumor cell growth, making the compounds useful in the treatment oftumors and viral diseases.

In addition to the ability to induce the production of cytokines, thecompounds affect other aspects of the innate immune response. Forexample, natural killer cell activity may be stimulated, an effect thatmay be due to cytokine induction. The compounds may also activatemacrophages, which in turn stimulates secretion of nitric oxide and theproduction of additional cytokines. Further, the compounds may causeproliferation and differentiation of B-lymphocytes.

Compounds of the invention also have an effect on the acquired immuneresponse. For example, although there is not believed to be any directeffect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the Th2 cytokine IL-5 is inhibited uponadministration of the compounds. This activity means that the compoundsare useful in the treatment of diseases where upregulation of the Th1response and/or downregulation of the Th2 response is desired. In viewof the ability of compounds of Formula I and Formula II to inhibitT-helper-type 2 immune response, the compounds are expected to be usefulin the treatment of atopy, e.g., atopic dermatitis, asthma, allergy,allergic rhinitis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

The immune response modifying effects of the compounds make them usefulin the treatment of a wide variety of conditions. Because of theirability to induce cytokines such as IFN-α and TNF-α, the compounds areparticularly useful in the treatment of viral diseases and tumors. Thisimmunomodulating activity suggests that compounds of the invention areuseful in treating diseases such as, but not limited to viral diseasese.g. genital warts, common, warts, plantar warts, Hepatitis B, HepatitisC, Herpes Simplex Type I and Type II, molluscum contagiosm, HIV, CMV,VZV, cervical intraepithelial neoplasia, human papillomavirus andassociated neoplasias; fungal diseases, e.g. candida, aspergillus,cryptococcal meningitis; neoplastic diseases, e.g., basal cellcarcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma,squamous cell carcinoma, myelogenous leukemia, multiple myeloma,melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and othercancers; parasitic diseases, e.g. pneumocystis carnii,cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection,leishmaniasis; bacterial infections, e.g., tuberculosis, mycobacteriumavium. Additional diseases or conditions that can be treated using thecompounds of the invention include eczema, eosinophilia, essentialthrombocythaemia, leprosy, multiple sclerosis, Ommen's syndrome,rheumatoid arthritis, systemic lupus erythematosis, discoid lupus,Bowen's disease and Bowenoid papulosis.

Accordingly, the invention provides a method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound of Formula I or Formula II to the animal. An amount of acompound effective to induce cytokine biosynthesis is an amountsufficient to cause one or more cell types, such as monocytes,macrophages, dendritic cells and B-cells to produce an amount of one ormore cytokines such as, for example, INF-<,TNF-<, IL-1,6,10 and 12 thatis increased over the background level of such cytokines. The preciseamount will vary according to factors known in the art but is expectedto be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10μg/kg to about 5 mg/kg. The invention further provides a method oftreating a viral infection in an animal comprising administering aneffective amount of a compound of Formula I or Formula II to the animal.An amount effective to treat or inhibit a viral infection is an amountthat will cause a reduction in one or more of the manifestations ofviral infection, such as viral lesions, viral load, rate of virusproduction, and mortality as compared to untreated control animals. Theprecise amount will vary according to factors known in the art but isexpected to be a dose of 100 ng/kg to about 50 mg/kg, preferably about10 μg/kg to about 5 mg/kg.

The invention is further described by the following examples, which areprovided for illustration only and are not intended to be limiting inany way.

EXAMPLE 1 Compound of Formula V 2-(5-Methyl-1H-tetrazol-1-yl)nicotinicAcid

Part A:

2-Aminonicotinic acid (5 g, 36 mmole) was suspended in acetic anhydride(25 mL) then heated at reflux for 2 hours. The reaction mixture wasconcentrated under vacuum. The resulting residue was slurried with ethylacetate and hexane then filtered to provide 5 g of2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one.

Part B:

The material from Part A was covered with acetic acid (75 mL), sodiumazide (2 g) was added and the reaction mixture was stirred at ambienttemperature over the weekend. The resulting precipitate was isolated byfiltration then dried to provide 5.6 g of2-(5-methyl-1H-tetrazol-1-yl)nicotinic acid as a white solid, m.p.178–180° C. (gas evolution). Analysis: Calculated for C₈H₇N₅O₂: % C,46.83; % H, 3.44; % N, 34.13; Found: % C, 46.38; % H, 3.36; % N, 34.01.

EXAMPLE 2 Compound of Formula VI Ethyl2-(5-Methyl-1H-tetrazol-1-yl)nicotinate

2-(5-Methyl-1H-tetrazol-1-yl)nicotinic acid (5.6 g, 27 mmole) wassuspended in acetone (250 mL), potassium carbonate (5 g) and ethyliodide (5 mL) were added and the reaction mixture was heated at refluxfor 2 hours. The acetone was removed under vacuum. The residue waspartitioned between water and dichloromethane. The dichloromethane layerwas separated, dried, then concentrated under vacuum to provide 6.3 g ofethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate.

EXAMPLE 3 Compound of Formula VII Tetrazolo[1,5-a][1,8]naphthyridin-5-ol

Ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole) wascovered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5 g,54 mmole) was added and the reaction mixture was stirred at ambienttemperature for 2 hours. The reaction mixture was poured into ice watercontaining about 17 mL of acetic acid. The resulting precipitate wasisolated by filtration, washed with water then dried to provide 4.5 g oftetrazolo[1,5-a][1,8]naphthyridin-5-ol as an off white solid, m.p. 236°(decomposition). Analysis: Calculated for C₈H₅N₅O: % C, 51.34; % H,2.69; % N, 37.42; Found: % C, 51.23; % H, 2.77; % N, 37.25.

EXAMPLE 4 5-Chlorotetrazolo[1,5-a][1,8]naphthyridine

Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspendedin phosphorous oxychloride (10 mL) and heated at reflux for 4 hours. Thereaction mixture was concentrated under vacuum and the residue waspoured into water. Dichloromethane was added and the aqueous layer wasmade basic with sodium bicarbonate. The dichloromethane layer wasseparated, dried over magnesium sulfate, filtered and then concentratedunder vacuum. The resulting solid was recrystallized from toluene toprovide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridine as a solid,m.p. 229–230° C. (decomposition). Analysis: Calculated for C₈H₄ClN₅: %C, 46.73; % H, 1.96; % N, 34.06; Found: % C, 46.87; % H 1.54; % N,33.93.

EXAMPLE 5 Compound of Formula VIII4-Nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol

Nitric acid (1.33 mL of 16M) was added to a suspension oftetrazolo[1,5-a][1,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid(50 mL). The reaction mixture was heated on a steam bath for 5 minutesthen cooled to ambient temperature. Sodium acetate (0.3 eq) in a smallamount of water was added to the reaction mixture. The resulting solidwas isolated by filtration and dried to provide 5 g of4-nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol as a solid, m.p. 278° C.(decomposition). Analysis: Calculated for C₈H₄N₆O₃+1.1H₂O: % C, 38.12; %H, 2.48; % N, 33.35; Found: % C, 37.99; % H, 2.41; % N, 32.82.

EXAMPLE 6 Compound of Formula XN⁵-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-amine

4-Nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol (3 g, 13 mmole) wassuspended in dichloromethane (3.8 mL), triethylamine (1.8 mL) was added,and the reaction mixture was cooled in an ice bath.Trifluoromethanesulfonic anhydride (2.2 mL) was added dropwise.Isobutylamine (3.8 mL) was added in a single aliquot and the reactionmixture exothermed. The reaction mixture was partitioned betweendichloromethane and aqueous sodium bicarbonate. The dichloromethanelayer was separated, dried over magnesium sulfate then filtered througha layer of silica gel. The silica gel was eluted first withdichloromethane then with 5% methanol in dichloromethane. The eluant wasevaporated to provideN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine asa yellow solid, m.p. 171° C. (decomposition). Analysis: Calculated forC₁₂H₁₃N₇O₂: % C, 50.17; % H 4.56; % N, 34.13; Found: % C, 49.84; % H,4.51; % N, 33.88.

EXAMPLE 7 Compound of Formula XIN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine

A catalytic amount of 5% platinum on carbon was added to a suspension ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine(2.45 g, 8.5 mmoles) in ethanol (120 mL). The reaction mixture wasreduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen for 2 hours.The reaction mixture was filtered to remove the catalyst. The filtratewas concentrated under vacuum to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as anoil.

EXAMPLE 8 Compound of Formula XII1-(2-Methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine

The N⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diaminefrom Example 7 was combined with diethoxymethylacetate (2 mL) and heatedon a steam bath for 3 hours. The reaction mixture was allowed to standat ambient temperature overnight and then it was diluted withdichloromethane and methanol. The resulting solution was heated toremove the dichloromethane and reduce the volume of methanol to 50 mLand then cooled. The resulting precipitate was isolated by filtration toprovide 1.2 g of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridineas a solid, m.p. 248–250° C. (decomposition). Analysis: Calculated forC₁₃H₁₃N₇: % C, 58.42; % H, 4.90; % N, 36.68; Found: % C, 58.04; % H,4.79; % N, 36.23.

EXAMPLE 9 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine hydrate

Part A:

Triphenylphosphine (1.0 g, 3.7 mmole) was added to a solution of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine(0.5 g, 1.87 mmole) in 1,2-dichlorobenzene (15 mL). The reaction mixturewas heated at reflux for 2 hours then concentrated under vacuum toremove the majority of the 1,2-dichlorobenzene. The residue was slurriedwith hexanes for 30 minutes. The resulting solid1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminewas isolated by filtration and dried.

Part B:

The1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminefrom Part A was dissolved in methanol (15 mL). Hydrochloric acid (10 mLof 0.6N) was added and the reaction mixture was heated at reflux for 1hour. The reaction mixture was concentrated under vacuum. The residuewas diluted with water then made basic with sodium bicarbonate. Theresulting solid was isolated by filtration, slurried with ether and thenisolated by filtration. The solid was suspended in toluene (25 mL). Thesuspension was heated to reflux then diluted with methanol (10 mL) todissolve the solid. The solution was refluxed to remove the methanolthen cooled to ambient temperature. The resulting precipitate wasisolated by filtration then coated onto silica gel. The silica gel waseluted with 10–20% methanol in ethyl acetate. The eluant wasconcentrated to dryness. The resulting material was recrystallized frommethanol and water to provide 0.35 g1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine hydrate asa solid, m.p. 325–330° C. (decomposition). Analysis: Calculated forC₁₃H₁₅N₅+¼H₂O: % C, 63.52; % H, 6.35; % N, 28.49; Found: % C, 64.02; %H, 5.87; % N, 28.23.

EXAMPLE 10 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][11,8]naphthyridin-4-amine

Platinum oxide catalyst was added to a solution of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridinein trifluoroacetic acid (30 mL). The reaction mixture was reduced on aParr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure for 5 hours. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated under vacuum. The residue was combined with water andsodium bicarbonate. The resulting precipitate was isolated byfiltration. The solid was dissolved in 1N hydrochloric acid and charcoalfiltered. The filtrate was treated with 10% sodium hydroxide. Theresulting precipitate was isolated by filtration then recrystallizedfrom ethyl acetate/methanol. The recrystallized material was dissolvedin dichloromethane/methanol and placed on a silica gel column. Thecolumn was eluted with 10% methanol in ethyl acetate. The eluant wasconcentrated under vacuum and the residue was recrystallized frommethanol/water to provide 0.9 g of6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amineas a solid, m.p. 231–233° C. Analysis: Calculated for C₁₃H₁₉N₅: % C,63.65; % H, 7.81; % N, 28.55; Found: % C, 62.99; % H, 7.74; % N, 28.33.

EXAMPLE 11 Compound of Formula XII2-Butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine

A catalytic amount of 5% platinum on carbon was added to a suspension ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (5g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced ona Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen for 2 hours. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated under vacuum to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as anoil.

The oil was covered with acetic acid (300 mL), valeryl chloride (2.1 mL,17.4 mmole) was added and the resulting mixture was heated at refluxovernight. The reaction mixture was concentrated under vacuum. Theresulting residue was taken up in dichloromethane, washed with sodiumbicarbonate, dried over magnesium sulfate then concentrated undervacuum. The residue was purified using flash chromatography (silica gel;eluting with 2–3% methanol in dichloromethane). The isolated product waspurified further using preparatory high performance liquidchromatography eluting with 2% methanol in dichloromethane to provide2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridineas a solid, m.p. 182–184° C. Analysis: Calculated for C₁₇H₂₁N₇: % C,63.14; % H, 6.55; % N, 30.32; Found: % C, 63.45; % H, 6.60; % N, 30.40.

EXAMPLE 12 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine

Triphenylphosphine (0.9 g, 3.7 mmole) was added to a solution of2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine(0.6 g, 1.8 mmole) in 1,2-dichlorobenzene (15 mL). The resulting mixturewas heated at reflux for 2 hours then concentrated under vacuum toremove most of the 1,2-dichlorobenzene. The residue was slurred withhexanes then taken up in dichloromethane and filtered through a layer ofsilica gel. The silica gel was eluted initially with dichloromethane toremove the 1,2-dichlorobenzene and then with 10% methanol indichloromethane to recover2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine.

The2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminewas taken up in methanol (15 mL), combined with hydrochloric acid (10 mLof 0.6N), and then heated at reflux for 1 hour. The methanol was removedunder vacuum. The residue was combined with water and 10% hydrochloricacid then filtered. The filtrate was neutralized with 10% sodiumhydroxide. The resulting precipitate was isolated by filtration anddried. The resulting solid was refluxed in toluene. The volume oftoluene was reduced and the product was allowed to crystallize out underan argon atmosphere to provide 0.25 g of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminehemihydrate, m.p. 237–240° C. Analysis: Calculated for C₁₇H₂₃N₅+½H₂O: %C, 68.66; % H, 7.79; % N, 23.55; Found: % C, 66.80; % H, 7.62; % N,23.46.

EXAMPLE 13 Compound of Formula II2-Butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine(2.0 g, 6.2 mmole) in trifluoroacetic acid (30 mL). The reaction mixturewas reduced on a Parr apparatus under 50 psi (3.5 Kg/cm²) hydrogenpressure. The reaction mixture was filtered to remove the catalyst. Thefiltrate was concentrated under vacuum. The residue was combined withwater, sodium bicarbonate and 10% sodium hydroxide. An oil was recoveredand purified using reverse phase high performance liquid chromatographyeluting with 30:70 buffer (7.68 g potassium phosphate, monobasic; 1.69 gof sodium hydroxide, 1 L of water):methanol to provide2-butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminehemihydrate as a solid, m.p. 81–84° C. Calculated for C₁₇H₂₇N₅+½H₂O: %C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.57; % H, 9.15; % N,22.53.

EXAMPLE 14 Compound of Formula XVIII3-(5-Methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid

3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) was suspended inacetic anhydride (250 mL) then heated at reflux for 2 hours. Thereaction mixture was concentrated under vacuum. The solid residue wasslurried with heptane then concentrated under vacuum. The resultingsolid was covered with acetic acid (300 mL), then sodium azide (23.5 g,0.36 mol) was added. The reaction exothermed to 50° C. The reactionmixture was allowed to stir at ambient temperature overnight. Theprecipitate was isolated by filtration then slurried with methanol andfiltered. The solid was dissolved in 10% sodium hydroxide. The solutionwas heated on a steam bath for 30 minutes, allowed to cool to ambienttemperature then neutralized with 6N hydrochloric acid. The resultingprecipitate was isolated by filtration, washed with water and dried toprovide 64.5 g of 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylicacid as an off white solid, m.p. 214–215° C. (decomposition).

EXAMPLE 15 Compound of Formula XIX Ethyl3-(5-Methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate

Dimethylformamide diethyl acetal (46 mL) was added to a suspension of3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid (36 g) indichloromethane (800 mL). The reaction mixture was stirred at ambienttemperature overnight then washed six times with water (500 mL), driedover magnesium sulfated, and concentrated under vacuum. The residue wasrecrystallized from ethyl acetate/hexanes to provide 40 g of ethyl3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate as a solid.

EXAMPLE 16 Compound of Formula XX Tetrazolo[1,5-a][1,7]naphthyridin-5-olhydrate

Potassium ethoxide (20.2 g) was added to a mixture of ethyl3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate (28 g) anddimethylformamide (280 mL). The reaction mixture was allowed to stir atambient temperature overnight then poured into cold dilute acetic acid.The resulting precipitate was collected, washed with water and dried toprovide 22.4 g of tetrazolo[1,5-a][1,7]naphthyridin-5-ol hydrate as asolid, m.p. 247–248° C. (decomposition). Analysis: Calculated forC₈H₅N₅O: % C, 46.83; % H, 3.44; % N, 34.13; Found: % C, 46.48; % H,3.42; % N, 34.03.

EXAMPLE 17 Compound of Formula XXI5-Chlorotetrazolo[1,5-a][1,7]naphthyridine

A suspension of tetrazolo[1,5-a][1,7]naphthyridin-5-ol (3.5 g) inphosphorous oxychloride (15 mL) was heated at 90° C. for 2 hours. Thereaction mixture was concentrated under vacuum. The residue was pouredinto ice water, dichloromethane was added followed by the addition of10% sodium hydroxide to neutral pH. The product was partitioned intodichloromethane. The dichloromethane layer was separated, dried overmagnesium sulfate then concentrated under vacuum to provide 3.8 g of5-chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176–177° C.Analysis: Calculated for C₈H₄ClN₅: % C, 46.73; % H, 1.96; % N, 34.06;Found: % C, 46.80; % H, 2.16; % N, 34.45.

EXAMPLE 18 Compound of Formula XXIIN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine

A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g) inisobutylamine (100 mL) was heated at reflux for several hours. Thereaction mixture was concentrated under vacuum. The residue was taken upin dichloromethane, washed with water, dried over magnesium sulfate thenconcentrated under vacuum. The residue was recrystallized from tolueneto give a material that was a mixture by thin layer chromatography. Thematerial was purified by flash chromatography, silica gel eluting withdichloromethane, 5–20% ethyl acetate in dichloromethane, and 10%methanol in dichloromethane. The fractions with the slower movingmaterial were concentrated to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid,m.p. 220–221° C. Analysis: Calculated for C₁₂H₁₄N₆: % C, 59.49; % H,5.82; % N, 34.69; Found: % C, 59.35; % H, 5.89; % N, 34.88.

EXAMPLE 19 Compound of Formula XXIIIN⁵-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine

Nitric acid (2 equivalents of 16M) was added to a solution ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine (2.0 g,8.26 mmol) in acetic acid. The reaction mixture was heated on a steambath for about an hour then concentrated under vacuum. The residue waspoured into ice water and the resulting mixture was neutralized withsodium bicarbonate. The resulting precipitate was extracted withdichloromethane. The dichloromethane extracts were combined, washed withwater, and dried over magnesium sulfate. Thin layer chromatographyindicated a mixture so the material was filtered through a layer ofsilica gel eluting with 5% ethyl acetate in dichloromethane. Thereaction was rerun on 4 g of starting material but using only oneequivalent of nitric acid. The resulting material was also a mixture.The material from both reactions was combined then purified by flashchromatography eluting with mixtures of hexanes/ethyl acetate. Thefractions containing the slower moving material were combined to provideabout 0.3 g ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine asa yellow solid, m.p. 173–174° C. Analysis: Calculated for C₁₂H₁₃N₇O₂: %C, 50.17; % H, 4.56; % N, 34.13; Found: % C, 49.85; % H, 4.53; % N,34.26.

EXAMPLE 20 Compound of Formula XXIVN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine

N⁵-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine(1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess ofsodium hydrogen sulfide was dissolved in a minimum of water and added tothe suspension. The reaction mixture turned red and all of the materialwent into solution. The reaction mixture was extracted twice withdichloromethane (150 mL). The extracts were combined, washed with water,dried over magnesium sulfate, filtered and concentrated under vacuum toprovide 1.22 g ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as alight yellow solid, m.p. 203–204.5° C. Analysis: Calculated for:C₁₂H₁₅N₇: % C, 56.02; % H, 5.88; % N, 38.11; Found: % C, 55.68; % H,5.81; % N, 37.74.

EXAMPLE 21 Compound of Formula XXV1-(2-Methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine

N⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (1.1 g,4.3 mmol) was combined with diethoxymethylacetate (2 mL) and heated on asteam bath overnight. The reaction mixture was partitioned betweendichloromethane and ammonium hydroxide. The dichloromethane layer wasseparated, washed with water, dried over magnesium sulfate andconcentrated under vacuum. The residue was recrystallized from ethylacetate/hexane to provide 0.85 g of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineas a solid, m.p. 181–182.5° C. Analysis: Calculated for C₁₃H₁₃N₇: % C,58.42; % H, 4.90; % N, 36.68; Found: % C, 58.87; % H, 5.04; % N, 36.13.

EXAMPLE 22 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

Part A:

Triphenylphosphine (0.49 g, 1.8 mmol) was added to a suspension of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine(0.24 g, 0.9 mmol) in dichlorobenzene (15 mL). The reaction mixture washeated at reflux overnight then concentrated under vacuum. The residuewas slurried with hexane and the resulting solid1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

Part B:

The1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part A was dissolved in methanol (30 mL). Hydrochloric acid (3 mLof 3N) was added to the solution and the reaction mixture was heated atreflux overnight before being concentrated under vacuum to remove themethanol. The aqueous residue was neutralized with sodium bicarbonatethen extracted with dichloromethane. The extract was dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5–10% methanolin dichloromethane) to provide 0.15 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as asolid, m.p. 306–307° C. Analysis: Calculated for C₁₃H₁₅N₅: % C, 64.71; %H, 6.27; % N, 29.02; Found: % C, 65.10; % H, 6.28; % N, 28.70.

EXAMPLE 23 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g,1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced ona Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure overnight. Thereaction mixture was filtered and washed with methanol to remove thecatalyst. The filtrate was concentrated under vacuum. The residue wascombined with dichloromethane and aqueous sodium bicarbonate was addeduntil the mixture was basic. The dichloromethane layer was separated.The aqueous layer was extracted five times with dichloromethane (100mL). The dichloromethane extracts were combined, dried over magnesiumsulfate and concentrated under vacuum. The resulting residue wasrecrystallized from toluene to provide 0.34 g of6,7,8,9-tetrahydro-1-[(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 220–223° C. Analysis: Calculated for C₁₃H₁₉N₅+¼H₂O: %C, 62.50% H, 7.87; % N, 28.03; Found: % C, 62.50; % H, 7.72; % N, 27.46.

EXAMPLE 24 Compound of Formula XXV2-Methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine

Acetic anhydride (2–3 mL) was added to a solution ofN-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (0.8 g,3.1 mmole) in acetic acid. The reaction mixture was heated on a steambath for several hours then concentrated under vacuum. The residue waspartitioned between dichloromethane and water. The aqueous layer wasmade basic with 10% sodium hydroxide then the dichloromethane layer wasseparated, dried over magnesium sulfate and concentrated under vacuum.The residue was purified by flash chromatography (silica gel elutingwith 2–5% methanol in dichloromethane) to provide 0.25 g of2-methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineas a solid, m.p. 157–158° C. Analysis: Calculated for C₁₄H₁₅N₇: % C,59.77; % H, 5.37; % N, 34.85; Found: % C, 59.64; % H, 5.48; % N, 34.98:

EXAMPLE 25 Compound of Formula I2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

Part A:

Triphenylphosphine (2.5 g, 9.6 mmol) was added to a suspension of2-methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine(1 g, 4 mmol) in dichlorobenzene. The reaction mixture was heated atreflux overnight then concentrated under vacuum. The residue wasslurried with hexane and the resulting solid2-methyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

Part B:

The2-methyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part A was dissolved in methanol (100 mL). Hydrochloric acid (10 mLof 3N) was added to the solution and the reaction mixture was heated atreflux overnight before being concentrated under vacuum to remove themethanol. The residue was purified by flash chromatography (silica geleluting with dichloromethane and gradually increasing the polarity to 5%methanol in dichloromethane) to provide2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 322–324° C. Analysis: Calculated for C₁₄H₁₇N₅: % C,65.86; % H, 6.71; % N, 27.43; Found: % C, 65.81; % H, 6.64; % N, 27.41.

EXAMPLE 26 Compound of Formula II6,7,8,9-Tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine(0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture wasreduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered and washed with methanol toremove the catalyst, and the filtrate was concentrated under vacuum. Theresidue was combined with dichloromethane and aqueous sodium bicarbonatewas added until the mixture was basic. The dichloromethane layer wasseparated, and the aqueous layer was extracted three times withdichloromethane (100 mL). The combined dichloromethane extracts weredried over magnesium sulfate and concentrated under vacuum. Theresulting residue was recrystallized from toluene to provide6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 226–230° C. Analysis: Calculated forC₁₄H_(2l)N₅+1.75H₂O: % C, 57.81; % H, 8.49; % N, 24.07; Found: % C,57.89; % H, 8.04; % N, 23.45.

EXAMPLE 27 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

Part A:

Valeryl chloride (0.76 mL, 6.4 mmol) was added to a solution ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (1.5 g,5.8 mmol) in acetonitrile (15 mL). The reaction mixture was allowed tostir at ambient temperature for several hours. The resulting precipitatewas isolated by filtration. Thin layer chromatography indicated that thematerial contained two components. The solid was dissolved in aceticacid and heated at reflux overnight. The reaction mixture wasconcentrated under vacuum, and the residue extracted withdichloromethane. The dichloromethane extract was washed with water,dried over magnesium sulfate and concentrated under vacuum to provide amixture of2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineand the acylated, but uncyclized intermediate.

Part B:

Triphenylphosphine (2.4 g) was added to a suspension of the materialfrom Part A in dichlorobenzene. The reaction mixture was heated atreflux overnight then concentrated under vacuum. The residue wasslurried with hexane and the resulting solid2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

Part C:

The2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part B was dissolved in methanol. Hydrochloric acid (3N) was addedto the solution and the reaction mixture was heated at reflux overnightbefore being concentrated under vacuum to remove the methanol. Theaqueous residue was mixed with dichloromethane then neutralized withaqueous sodium bicarbonate. The dichloromethane layer was separated,dried over magnesium sulfate and concentrated under vacuum. The residuewas purified by flash chromatography (silica gel eluting withdichloromethane and gradually increasing the polarity to 5% methanol indichloromethane) to provide2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine asa solid, m.p 213–214° C. Analysis: Calculated for C₁₇H₂₃N₅: % C, 68.66;% H, 7.80; % N, 23.55; Found: % C, 68.26; % H, 7.69; % N, 23.41.

EXAMPLE 28 Compound of Formula II2-Butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine(0.5 g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixturewas reduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered and washed with methanol toremove the catalyst. The filtrate was concentrated under vacuum. Theresidue was combined with dichloromethane and aqueous sodium bicarbonatewas added until the mixture was basic. The dichloromethane layer wasseparated. The aqueous layer was extracted three times withdichloromethane (100 mL). The dichloromethane extracts were combined,dried over magnesium sulfate and concentrated under vacuum. Theresulting residue was recrystallized from toluene then purified by flashchromatography (silica gel eluting with 20% methanol in dichloromethanewith a trace of ammonium hydroxide) to provide6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 164–166° C. Analysis: Calculated for C₁₇H₂₇N₅+0.5H₂O: %C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.99; % H, 8.71; % N,22.23.

EXAMPLE 29 Compound of Formula XXXIN⁴-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amine

Phosphorous oxychloride (0.6 mL, 6.44 mmol) was reacted withN,N-dimethylformamide then added to a solution of3-nitro[1,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was warmed using ajacketed flask with refluxing acetone as a heat source. After 3 hoursthe reaction mixture was poured into ice water, isobutylamine (2.0 mL,20.1 mmol) was added and the mixture was heated on a steam bath. Afterseveral hours the reaction mixture was cooled to ambient temperature,filtered and washed with water. The aqueous layer was extracted withdichloromethane. The dichloromethane extract was washed with aqueoussodium bicarbonate, washed with water, dried over magnesium filtratethen loaded onto a layer of silica gel. The silica gel was elutedinitially with dichloromethane to remove an impurity then with 5%methanol in dichloromethane to recover the product. The eluant wasconcentrated to dryness to provideN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a solid, m.p.97–99° C.

EXAMPLE 30 Compound of Formula XXXIII1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

Part A:

A catalytic amount of 5% platinum on carbon was added to a solution ofN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (1.0 g, 4.1 mmol)in ethyl acetate (50 mL). The reaction mixture was reduced on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. The reactionmixture was filtered to remove the catalyst and the filtrate wasconcentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

Part B:

The crude solid from Part A was combined with diethoxymethylacetate (2mL) then heated on a steam bath overnight. The reaction mixture wastaken up in dichloromethane, washed with water, dried over magnesiumsulfate then filtered through a layer of silica gel. The silica gel waseluted with dichloromethane to remove excess diethoxymethylacetate thenwith 5% methanol in dichloromethane to recover the product. The eluantwas concentrated to provide an oil which was purified by flashchromatography (silica gel eluting with 50% ethyl acetate/hexane thenwith ethyl acetate) to provide 0.25 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a solid m.p.82–84° C. Analysis: Calculated for C₁₃H₁₄N₄: % C, 69.00; % H, 6.24; % N,24.76; Found: % C, 68.79; % H, 6.44; % N, 24.73.

EXAMPLE 31 Compound of Formula XXXIV1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperoxybenzoic acid (3.7 g of 50%) was added in small portionsover a period of 30 minutes to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.5 g) inchloroform at ambient temperature. After 3 hours the reaction mixturewas diluted with chloroform, washed twice with 2.0 M sodium hydroxideand once with water, dried over magnesium sulfate then concentratedunder vacuum. The residue was recrystallized from ethyl acetate/hexaneto provide 1.2 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide as asolid, m.p. 183–185° C. Analysis: Calculated for C₁₃H₁₄N₄O: % C, 64.45;% H, 5.82; % N, 23.12; Found: % C, 64.15; % H, 5.92; % N, 23.02.

EXAMPLE 32 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Ammonium hydroxide (10 mL) was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide (0.6 g)in dichloromethane (30 mL). The reaction mixture was cooled in an icebath then tosyl chloride (0.5 g) in dichloromethane was added while thereaction was being rapidly stirred. The reaction mixture was stirred atambient temperature overnight. The dichloromethane layer was separated,washed with aqueous sodium bicarbonate, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromethyl acetate/hexane to provide 0.2 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as asolid, m.p. 230–231.5° C. Analysis: Calculated for C₁₃H₁₅N₅: % C, 64.71;% H, 6.27; % N, 29.02; Found: % C, 64.70; % H, 6.01; % N, 29.08.

EXAMPLE 33 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g)in trifluoroacetic acid (10 mL). The reaction mixture was reduced on aParr apparatus under 45 psi (3.15 Kg/cm²) hydrogen pressure for 4 hours.The reaction mixture was filtered to remove the catalyst and thefiltrate was concentrated under vacuum. The residue was combined withaqueous sodium bicarbonate then a small amount of 10% sodium hydroxidewas added. The resulting precipitate was extracted with dichloromethane.The dichloromethane extract was dried over magnesium sulfate thenconcentrated under vacuum. The residue was purified by flashchromatography (silica gel eluting with 5% methanol in dichloromethanecontaining 0.5% ammonium hydroxide). The eluant was concentrated undervacuum. The residue was recrystallized from ethyl acetate to provide6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 222–226° C. Analysis: Calculated for C₁₃H₁₉N₅: % C,63.65; % H, 7.81; % N, 28.55; Found: % C, 63.07; % H, 7.51; % N, 28.00.

EXAMPLE 34 Compound of Formula XXXIII2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

Part A:

Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbonwere added to a solution ofN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (4.0 g, 16.2 mmol)in ethyl acetate (250 mL). The reaction mixture was reduced on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. The reactionmixture was filtered to remove the catalyst and the filtrate wasconcentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

Part B:

The crude solid from Part A was taken up in acetic acid, combined withacetic anhydride then heated at reflux overnight. The reaction mixturewas concentrated under vacuum. The resulting residue was combined withmethanol to decompose excess acetic anhydride then concentrated undervacuum. The resulting residue was combined with cyclohexane thenconcentrated under vacuum to remove the acetic acid. The resultingresidue was recrystallized from hexanes to provide 2.2 g of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine asoff-white needles, m.p. 118–119° C. Analysis: Calculated for C₁₄H₁₆N₄: %C, 69.97; % H, 6.71; % N, 23.31; Found: % C, 69.24; % H, 6.67; % N,23.23.

EXAMPLE 35 Compound of Formula XXXIV2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperoxybenzoic acid (4.5 g of 50%, 13.1 mmol) was added in smallportions over a period of 30 minutes to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.1 g,8.7 mmole) in chloroform at ambient temperature. After 3 hours thereaction mixture was diluted with chloroform, washed twice with 2.0 Msodium hydroxide, once with water, and once with brine, dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5% methanol indichloromethane) to provide2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a solid, m.p. 228–230° C. Analysis: Calculated for C₁₄H₁₆N₄O: % C,65.61; % H, 6.29; % N, 21.86; Found: % C, 65.73; % H, 6.31; % N, 21.95.

EXAMPLE 36 Compound of Formula I

-   2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Ammonium hydroxide (10 mL) was added to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.1 g, 4.29 mmol) in dichloromethane (50 mL). The reaction mixture wascooled in an ice bath then tosyl chloride (0.82 g, 4.29 mmol) indichloromethane was added. The reaction was warmed to about 30° C. whilebeing rapidly stirred. The reaction mixture was stirred at ambienttemperature overnight. The dichloromethane layer was separated, washedwith 10% sodium hydroxide, water and brine, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromethyl acetate to provide 0.8 g of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 228–230° C. Analysis: Calculated for C₁₄H₁₇N₅: % C,65.86; % H, 6.71; % N, 27.43; Found: % C, 65.65; % H, 6.69; % N, 27.59.

EXAMPLE 37 Compound of Formula XXXIII2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

Part A:

Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbonwere added to a solution ofN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (3.0 g, 12.2 mmol)in ethyl acetate (150 mL). The reaction mixture was reduced on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. The reactionmixture was filtered to remove the catalyst and the filtrate wasconcentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

Part B:

The crude solid from Part A was taken up in acetonitrile then combinedwith valeryl chloride (1.5 mL, 12.2 mmol). The mixture was stirred atambient temperature for 30 minutes. The resulting precipitate wasisolated by filtration, washed with a small amount of acetonitrile andair dried to provide 2.75 g ofN-(4-(2-methylpropylamino)[1,5]naphthyridin-3-yl)valeramidehydrochloride as a solid.

Part C:

The solid from Part B was suspended in acetic acid and heated at refluxovernight. The reaction mixture was concentrated under vacuum and theresulting residue was partitioned between dichloromethane and aqueoussodium bicarbonate. The dichloromethane layer was separated, dried overmagnesium sulfate and concentrated under vacuum to provide 2.3 g of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as anoil.

EXAMPLE 38 Compound of Formula XXXIV2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperoxybenzoic acid (5.3 g of 50%, 15.2 mmol) was added in smallportions over a period of 30 minutes to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.3 g,10.2 mmole) in chloroform at ambient temperature. After 3 hours thereaction mixture was diluted with chloroform, washed twice with 2.0 Msodium hydroxide, once with water, and once with brine, dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5% methanol indichloromethane) to provide2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.Analysis: Calculated for C₁₇H₂₂N₄O: % C, 68.43; % H, 7.43; % N, 18.78;Found: % C, 67.67; % H, 6.73; % N, 18.13.

EXAMPLE 39 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Ammonium hydroxide (25 mL) was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(2.0 g, 6.7 mmol) in dichloromethane (100 mL). The reaction mixture wascooled in an ice bath then tosyl chloride (1.3 g, 6.7 mmol) indichloromethane was added. The reaction was warmed to about 30° C. whilebeing rapidly stirred. The reaction mixture was stirred at ambienttemperature overnight. The dichloromethane layer was separated, washedwith 10% sodium hydroxide, water and brine, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromhexane to provide 1.55 g of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa solid, m.p. 115–116° C. Analysis: Calculated for C₁₇H₂₃N₅: % C, 68.66;% H, 7.80; % N, 23.55; Found: % C, 69.52; % H, 7.72; % N, 21.72.

EXAMPLE 40 Compound of Formula II6,7,8,9-Tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

A catalytic amount of platinum oxide was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine(0.5 g) in trifluoroacetic acid (15 mL). The reaction mixture wasreduced on a Parr apparatus under 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered to remove the catalyst andthe filtrate was concentrated under vacuum. The residue was combinedwith aqueous sodium bicarbonate then a small amount of 10% sodiumhydroxide was added. The resulting precipitate was extracted withdichloromethane. The dichloromethane extract was dried over magnesiumsulfate then concentrated under vacuum. The residue was purified byflash chromatography (silica gel eluting with 1–5% methanol indichloromethane containing 0.5% ammonium hydroxide). The eluant wasconcentrated under vacuum. The residue was recrystallized fromhexane/ethyl acetate to provide6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 143–147° C. Analysis: Calculated for C₁₇H₂₇N₅: % C,67.74; % H, 9.03; % N, 23.23; Found: % C, 61.90; % H, 7.51; % N, 19.91.

EXAMPLE 41 Compound of Formula XXXI 1,1-DimethylethylN-{4-[(3-Nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate

Phosphorus oxychloride (4 mL, 0.31 mole) was combined withN,N-dimethylformamide (100 mL) while cooling in an ice bath. Theresulting mixture was added to a solution of3-nitro[1,5]naphthyridin-4-ol (50 g, 0.26 mole) in N,N-dimethylformamide(500 mL). The reaction mixture was stirred at ambient temperature for 6hours. The reaction mixture was poured into ice water and then extractedwith dichloromethane (1800 mL). The organic layer was separated and thencombined with triethylamine (45 mL). Tert-butylN-(4-aminobutyl)carbamate was added and the reaction mixture was stirredovernight. The reaction mixture was concentrated under vacuum and theresidue was treated with water (˜1500 mL). The resulting solid wasisolated by filtration, washed with water and dried to provide 76 g of1,1-dimethylethylN-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a solid. Asmall sample was recrystallized from isopropyl alcohol to provide a puresample, m.p. 137–138° C. Analysis: Calculated for C₁₇H₂₃N₅O₄: % C,56.50; % H, 6.41; % N, 19.38; Found: % C, 56.26; % H, 6.30; % N, 19.53.

EXAMPLE 42 Compound of Formula XXXII 1,1-DimethylethylN-{4-[(3-Amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate

1,1-DimethylethylN-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate (42.7 g, 0.12mole), platinum on carbon (2 g) and ethyl acetate (500 mL) were combinedand then hydrogenated on a Parr apparatus at 30 psi (2.1 Kg/cm²)hydrogen pressure for 1 hour. The catalyst was removed by filtration andrinsed with ethyl acetate. The filtrate was concentrated under vacuum toprovide 1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a brightyellow-orange solid.

EXAMPLE 43 Compound of Formula XXXIII 1,1-DimethylethylN-[4-(2-Butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) was addedto a mixture of 1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (39 g, 0.12mole) in warm xylene (500 mL). The reaction mixture was heated at refluxovernight. Thin layer chromatography showed that at least half of thestarting material was still present. p-Toluenesulfonic anhydridemonohydrate (6 g) was added. After a short time thin layerchromatography showed that the reaction was complete. The reactionmixture was allowed to cool to ambient temperature and then it wasdiluted with ethyl acetate and washed with aqueous sodium bicarbonate.The organic layer was concentrated under vacuum to provide an oilyresidue. The residue was triturated with hexane to provide a dark pinksolid. This solid was recrystallized from acetonitrile to provide1,1-dimethylethylN-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate asa pale peach solid, m.p. 96.0–98.0° C. Analysis: Calculated forC₂₂H₃₁N₅O₂: % C, 66.47; % H, 7.86; % N, 17.62; Found: % C, 66.29; % H,7.78; % N, 17.76.

EXAMPLE 44 Compound of Formula XXXIV1-{4-[(1,1-Dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (1 eq at 57%) was added in portions to asolution of 1,1-dimethylethylN-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate inchloroform (50 mL). The reaction mixture was allowed to stir at ambienttemperature for 2 hours at which time thin layer chromatography showedthat no starting material remained. The reaction mixture was dilutedwith dichloromethane and then washed twice with 1 M sodium hydroxide.The organic layer was dried over anhydrous magnesium sulfate and thenconcentrated under vacuum to provide1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas an orange oil which solidified on standing.

EXAMPLE 45 Compound of Formula I 1,1-DimethylethylN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Ammonium hydroxide (20 mL) was added to a solution of1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(19.4 g) in chloroform. Tosyl chloride (9 g) was slowly added. Thinlayer chromatography indicated that the reaction was proceeding slowly.Additional tosyl chloride was added twice. After thin layerchromatography indicated that the reaction was complete, the layers wereseparated. The organic layer was washed with dilute aqueous sodiumcarbonate, dried over magnesium sulfate and then concentrated undervacuum. The residue was covered with methyl acetate (10 mL), hexane (5mL) was added and the mixture was allowed to stand overnight. Theresulting crystalline solid was isolated by filtration, washed withhexane and then dried to provide 15.1 g of 1,1-dimethylethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate,m.p. 148.5–149.5° C. Analysis: Calculated for C₂₂H₃₂N₆O₂: % C, 64.05; %H, 7.82; % N, 20.37; Found: % C, 64.15; % H, 7.82; % N, 20.55.

EXAMPLE 46 Compound of Formula I4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine

A suspension of 1,1-dimethylethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate(13.8 g) in 1N hydrochloric acid (140 mL) was heated on a steam bath for1.5 hours. The reaction mixture was allowed to cool to ambienttemperature and then it was made basic (pH>11) with 50% sodiumhydroxide. The resulting precipitate was isolated by filtration, washedwith water and then dried to provide 9.5 g of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamineas a white solid, m.p. 212–213° C. Analysis: Calculated for C₁₇H₂₄N₆: %C, 65.36; % H, 7.74; % N, 26.90; Found: % C, 65.16; % H, 7.65; % N,27.29.

EXAMPLE 47 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea

Under a nitrogen atmosphere, phenyl isocyanate (52 μL, 0.48 mmol) wasadded to a suspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reactionmixture was stirred for 20 minutes at which time it had turnedhomogeneous and thin layer chromatography indicated no starting materialremained. Aminomethyl resin (280 mg of 1% cross linked, 100–200 meshavailable from BACHEM, Torrance, Calif.) was added and the reactionmixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added andthe mixture was concentrated under vacuum to provide a solid. The solidwas purified by flash chromatography eluting with 95/5dichloromethane/methanol to give a white solid which was dried undervacuum at 60° C. to provide 0.12 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea.Analysis: Calculated for C₂₄H₂₉N₇O+⅕H₂O: % C, 66.25; % H, 6.81; % N,22.53; Found: % C, 66.27; % H, 6.63; % N, 22.83.

EXAMPLE 48 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylurea

Using the general method of Example 47, cyclohexyl isocyanate (61 μL,0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.14 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylureaas a white solid. Analysis: Calculated for C₂₄H₃₅N₇O: % C, 65.88; % H,8.06; % N, 22.41. ¹H NMR (300 MHz, CDCl₃) δ 8.60 (dd, J=4.4, 1.4 Hz,1H), 8.08 (d, J=8.5 Hz, 1H), 7.44 (dd, J=8.5; 4.4 Hz, 1H), 5.55 (br s,2H), 4.92 (t, J=5.8 Hz, 1H), 4.82 (apparent t, J=7.8 Hz, 2H), 4.13 (d,J=8.6 Hz, 1H), 3.48 (m, 1H), 3.35 (apparent q, J=6.4 Hz, 2H), 2.93(apparent t, J=7.8 Hz, 2H), 1.80–2.05 (m, 4H), 1.45–1.75 (m, 6H),1.2–1.4 (m 2H), 1.0–1.2 (m, 2 H), 1.03 (t, 7.4 Hz, 3H); HRMS (EI) calcdfor C₂₄H₃₅N₇O (M⁺) 437.2903, found 437.2903.

EXAMPLE 49 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylurea

Using the general method of Example 47, butyl isocyanate (54 μL, 0.48mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.13 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylureaas a white solid. Analysis: Calculated for C₂₂H₃₃N₇O: % C, 64.21; % H,8.08; % N, 23.82; Found: % C, 64.05; % H, 7.97; % N, 24.00.

EXAMPLE 50 Compound of Formula I PhenylN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Using the general method of Example 47, phenyl chloroformate (61 μL,0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.12 g of phenylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a solid. Analysis: Calculated for C₂₄H₂₈N₆O₂: % C, 66.65; % H, 6.53;% N, 19.43; Found: % C, 66.49; % H, 6.59; % N, 19.32.

EXAMPLE 51 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide

Using the general method of Example 47, furoyl chloride (15.8 μL, 0.16mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.05 g, 0.16 mmole) to provide 0.019 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.58 (dd, J=4.4, 1.5 Hz,1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1H), 7.33(m, 1H), 7.08 (dd, J=3.5, 0.6 Hz, 1H), 6.84 (m, 1H), 6.47 (dd, J=3.5,1.7 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 2H), 3.59 (apparent q, J=6.5Hz, 2H), 2.92 (apparent t, J=7.8 Hz, 2H), 1.7–2.1(m, 6H), 1.51 (m, 2H);1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C₂₂H₂₆N₆O₂ (M⁺) 406.2117,found 406.2121.

EXAMPLE 52 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamide

Using the general method of Example 47, benzoyl chloride (56 μL, 0.48mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.11 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamideas a white solid. Analysis: Calculated for C₂₄H₂₈N₆O+¼H₂O: % C, 68.47; %H, 6.82; % N, 19.96: Found: % C, 68.24; % H, 6.76; % N, 19.90.

EXAMPLE 53 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylurea

Benzyl isocyanate (59 μL, 0.48 mmol) was added at ambient temperature toa suspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL). A solution was obtainedin less than 30 minutes and thin layer chromatography (9:1dichloromethane:methanol) showed one major new spot with a higher R_(f)and only a trace of starting material. Aminomethyl resin (280 mg) wasadded and the reaction mixture was stirred for 15 minutes. The solventwas removed under vacuum. The residue was purified by columnchromatography to provide 0.16 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylureaas a white solid. Analysis: Calculated for C₂₅H₃₁N₇O: % C, 67.39; % H,7.01; % N, 22.00; Found: % C, 67.43; % H, 6.92; % N, 22.02.

EXAMPLE 54 Compound of Formula IN³-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamide

4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.050 g, 0.16 mmol) was suspended in tetrahydrofuran (30 mL).N,N-diisopropylethylamine (28 μL, 0.16 mmol) was added to the suspensionand then nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) wasadded. The reaction mixture was stirred at ambient temperature for 1hour by which time a solution was obtained. Thin layer chromatography(9:1 dichloromethane:methanol) showed one major new spot with a higherR_(f) and only a trace of starting material. Aminomethyl resin (100 mg)was added and the reaction mixture was stirred for 5 minutes. Thesolvent was removed under vacuum. The residue was dissolved indichloromethane and placed on a layer of silica gel. The silica gel waseluted first with dichloromethane and then with 9:1dichloromethane:methanol. The cleanest fractions were combined and thenconcentrated under vacuum to provideN³-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamideas a white powder. ¹H NMR (300 MHz, CDCl₃)™ 8.91 (m, 1H), 8.68 (d, J=4.5Hz, 1H), 8.45 (d, J=4.3 Hz, 1H), 8.03 (m, 2H), 7.30–7.40 (m, 2H), 6.98(s, 2H), 5.51 (s, 1H), 4.86 (apparent t, J=7.9 Hz, 2H), 3.66 (q, J=6.5Hz, 2H), 2.92 (apparent t, J=7.7 Hz, 2H), 2.05 (m, 2H), 1.75–1.95 (m,4H), 1.51 (m, 2H), 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C₂₃H₂₇N₇O(M⁺) 417.2277, found 417.2276.

EXAMPLE 55 Compound of Formula IN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c[1,5]naphthyridin-1-yl)butyl]phenylaceatamide

Phenylacetyl chloride (21 μL, 0.16 mmol) was added to a suspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.050 g, 0.16 mmol) in tetrahydrofuran (30 mL). The reaction mixturewas stirred at ambient temperature for 1 hour by which time a solutionwas obtained. Thin layer chromatography (9:1 dichloromethane:methanol)showed one major new spot with a higher R_(f) and only a trace ofstarting material. Aminomethyl resin (100 mg) was added and the reactionmixture was stirred for 5 minutes. The solvent was removed under vacuumto provide a white powder. This material was placed on a short column ofsilica gel and purified by eluting first with dichloromethane and thenwith 9:1 dichloromethane:methanol. The cleanest fractions were combinedand then concentrated under vacuum to provide a colorless oil. The oilwas dissolved in dichloromethane, hexane was added just until thesolution started to become cloudy, and then the solvent was removed toprovideN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]phenylacetamideas a white powder. Analysis: Calculated for C₂₅H₃₀N₆O₂: % C, 67.24; % H,6.77; % N, 18.82; Found: % C, 67.52; % H, 6.85; % N, 18.38. ¹H NMR (300MHz, CDCl₃)™ 8.51 (dd, J=4.4, 1.5 Hz, 1H), 8.11 (dd, J=8.4, 1.4 Hz, 1H),7.43 (dd, J=8.4, 4.4 Hz, 1H), 7.10–7.20 (m, 5H), 6.30 (br s, 2H), 5.83(m, 1H), 4.72 (apparent t, J=7.8 Hz, 2H), 3.54 (s, 2H), 3.35 (apparentq, J=6.5 Hz, 2H), 2.88 (apparent t, J=7.8 Hz, 2H), 1.80–1.90 (m, 4H),1.45–1.65 (m, 4H), 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C₂₅H₃₀N₆O(M⁺) 430.2481, found 430.2490.

EXAMPLE 56 Compound of Formula I BenzylN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Using the general method of Example 55, benzyl chloroformate (83 μL,0.58 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) to provide 0.18 g of benzylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder.

EXAMPLE 57 Compound of Formula I 9H-9-FluorenylmethylN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Using the general method of Example 55, 9-fluorenylmethyl chloroformate(0.085 g, 0.33 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder. Analysis: Calculated for C₃₂H₃₄N₆O₂+¼H₂O: % C, 71.29;% H, 6.45; % N, 15.59; Found: % C, 70.99; % H, 6.35; % N, 15.55.

EXAMPLE 58 Compound of Formula I EthylN-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

Using the general method of Example 55, ethyl chloroformate (46 μL, 0.48mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) to provide 0.15 g of ethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder. Analysis: Calculated for C₂₀H₂₈N₆O₂: % C, 62.48; % H,7.34; % N, 21.86; Found: % C, 61.73; % H, 7.28; % N, 21.62.

5 EXAMPLE 59 Compound of Formula XXXI1,1-Dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol

Phosphorus oxychloride (4 mL, 43 mmol) was reacted withN,N-dimethylformamide (15 mL) while chilling in an ice bath. Thismixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.9 g,36.1 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture waswarmed in an oil bath to 60° C. After 3 hours the reaction mixture waspoured into ice water. The resulting precipitate was isolated byfiltration and then washed with water. The wet crude5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150mL). Diisopropylethylamine was added followed by the slow addition ofhydroxyisobutylamine (3.4 g, 40 mmol). The reaction mixture was refluxedfor 2 hours and then combined with water (˜100 mL). The resultingprecipitate was isolated by filtration to provide 7.2 g of1,1-dimethyl-2-[(3-nitro[]1,5]naphthyridin-4-yl)amino]ethanol. A smallsample was recrystallized from isopropanol to provide a pure sample,m.p. 184.5–186° C. Analysis: Calculated for C₁₂H₁₄N₄O₃: % C, 54.96; % H,5.38; % N, 21.36; Found: % C, 54.63; % H, 5.36: % N, 21.51.

EXAMPLE 60 Compound of Formula XIII1,1-Dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol

Part A

A catalytic amount of 5% platinum on carbon was added to a suspension of1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (7 g, 26mmol) in isopropanol (300 mL). The mixture was hydrogenated on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure for 3 hours. Thereaction mixture was fileted to remove the catalyst. The filtrate wasconcentrated under vacuum. Toluene was added to the residue and themixture was concentrated under vacuum to remove all of the alcohol andprovide crude1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol.

Part B

Trimethylorthovalerate (3.6 mL, 20 mmol) was added to a suspension of1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13mmol) in xylene (100 mL). The reaction mixture was heated at reflux fortwo days. The mixture was diluted with methanolic ammonia, placed in aParr vessel and then heated at 110° C. for 4 hours. The reaction mixturewas concentrated under vacuum. The residue was partitioned betweendichloromethane and water. The layers were separated. The organic layerwas washed with water, dried over magnesium sulfate and thenconcentrated under vacuum to provide an oil. The oil was recrystallizedfrom methyl acetate/benzene to provide 2.8 g of1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol as a solid, m.p.85–88.5° C. Analysis: Calculated for C₁₇H₂₂N₄O: % C, 68.43; % H, 7.43; %N, 18.78; Found: % C, 68.04; % H, 7.18; % N, 19.09.

EXAMPLE 61 Compound of Formula XXXIV2-Butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (2.6 g, 9.5 mmol) was added in 3 portions to asolution of 1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol (2.6 g,8.7 mmol) in chloroform (50 mL) in a flask covered with aluminum foil.The reaction mixture was stirred at ambient temperature for 4 hours;then it was washed twice with dilute aqueous sodium bicarbonate, washedwith brine, dried over magnesium sulfate and then concentrated undervacuum. The residue was recrystallized from methyl acetate to provide2.25 g of2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide,m.p. 156–158° C. Analysis: Calculated for: C₁₇H₂₂N₄O₂+¼H₂O: % C, 64.03;% H, 7.11; % N, 17.57; Found: % C, 63.96; % H, 6.84; % N, 17.71.

EXAMPLE 62 Compound of Formula I1,1-Dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-1-yl)ethanol

Ammonium hydroxide (15 mL) was added to a solution of2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.9 g, 6.0 mmol) in dichloromethane (40 mL). Tosyl chloride (1.2 g, 6.4mmol) was slowly added. Thin layer chromatography indicated that thereaction was proceeding slowly. Additional tosyl chloride was addedtwice. After thin layer chromatography indicated that the reaction wascomplete, the layers were separated. The organic layer was washed withdilute aqueous sodium carbonate, dried over magnesium sulfate and thenconcentrated under vacuum. The residue was covered with methyl acetate(10 mL), hexane (5 mL) was added and the mixture was allowed to standovernight. The resulting crystalline solid was isolated by filtration toprovide 0.9 g of1,1-dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-1-yl)ethanol, m.p.177–179° C. Analysis: Calculated for C₁₇H₂₃N₅O: % C, 65.15; % H, 7.40; %N, 22.35; Found: % C, 64.97; % H, 7.33; % N, 22.71.

EXAMPLE 63 Compound of Formula XXXIII1,1-Dimethyl-2-(2-phenylemethyl[1,5]napthyridin-1-yl)ethanol

Part A

Phenylacetyl chloride (2.0 mL, 20 mmol) was added to a suspension of1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13mmol) in dichloromethane (100 mL). The reaction mixture was heated atreflux until thin layer chromatography indicated that the reaction wascomplete. The reaction mixture was taken on to the next step.

Part B

The material from Part A was combined with 7% ammonia in methanol (100mL), placed in a sealed vessel, and then heated at 150° C. for 6 hours.The reaction mixture was concentrated under vacuum. The residue wascombined with water (100 mL) and then extracted with dichloromethane(2×75 mL). The extracts were combined, washed with water (100 mL), driedover magnesium sulfate and then concentrated under vacuum. The residuewas recrystallized from methyl acetate to provide 2.1 g of1,1-dimethyl-2-(2-phenylmethyl[1,5]napthyridin-1-yl)ethanol as a solid,m.p. 150–152° C. Analysis: Calculated for C₂₀H₂₀N₄O: % C, 72.27; % H,6.06; % N, 16.85; Found: % C, 72.11; % H, 6.01; % N, 17.00.

EXAMPLE 64 Compound of Formula XXXIV2-Phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (1.8 g, 6.6 mmol) was added in 3 portions to asolution of 1,1-dimethyl-2-(2-phenylmethyl[1,5]napthyridin-1-yl)ethanol(2 g, 6 mmol) in chloroform (50 mL) in a flask covered with aluminumfoil. The reaction mixture was stirred at ambient temperature overnight;then it was washed twice with dilute aqueous sodium bicarbonate, washedwith brine, dried over magnesium sulfate and then concentrated undervacuum. The residue was recrystallized from isopropanol to provide 2.25g of2-phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide,m.p. 204–206° C. Analysis: Calculated for: C₂₀H₂₀N₄O₂+½H₂O: % C, 67.21;% H, 5.92; % N, 15.68; Found: % C, 67.05; % H, 5.65; % N, 15.39.

EXAMPLE 65 Compound of Formula I1,1-Dimethyl-2-(4-amino-2-phenylmethyl[1,5]napthyridin-1-yl)ethanol

Ammonium hydroxide (10 mL) was added to a solution of2-phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.5 g, 4.3 mmol) in dichloromethane (40 mL). Tosyl chloride (0.8 g, 4.3mmol) was slowly added. Thin layer chromatography indicated that thereaction was proceeding slowly. Additional tosyl chloride was addedtwice. After thin layer chromatography indicated that the reaction wascomplete, the layers were separated. The organic layer was washed withdilute aqueous sodium carbonate, dried over magnesium sulfate and thenconcentrated under vacuum. The residue was covered with methyl acetate(10 mL), hexane (5 mL) was added and the mixture was allowed to standovernight. The resulting crystalline solid was isolated by filtration toprovide1,1-dimethyl-2-(4-amino-2-phenylmethyl[1,5]napthyridin-1-yl)ethanol,m.p. 211–213° C. Analysis: Calculated for C₂₀H₂₁N₅O: % C, 69.14, % H,6.09; % N, 20.16; Found: % C, 69.10; % H, 6.12; % N, 20.48.

EXAMPLE 66 Compound of Formula XXXIN-Phenylmethyl-3-nitro[1,5]naphthyridin-4-amine

Phosphorus oxychloride (3.5 mL, 37.7 mmol) was reacted withN,N-dimethylformamide (15 mL) while chilling in an ice bath. Thismixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.0 g,31.4 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture waswarmed in an oil bath to 60° C. After 3 hours the reaction mixture waspoured into ice water. The resulting precipitate was isolated byfiltration and then washed with water. The wet crude5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150mL). Diisopropylethylamine (1.2 eq) was added followed by the slowaddition of benzylamine (4.7 mL g, 40 mmol). The reaction mixture wasrefluxed for 2 hours and then combined with water (˜100 mL). The layerswere separated and the organic layer was concentrated under vacuum toprovide 5.5 g of N-phenylmethyl-3-nitro[1,5]naphthyridin-4-amine. Asmall sample was recrystallized from isopropanol to provide a puresample, m.p. 127–129° C. Analysis: Calculated for C₁₅H₁₂N₄O₂: % C,64.28; % H, 4.32; % N, 19.99; Found: % C, 63.89; % H, 4.40: % N, 20.35.

EXAMPLE 67 N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamideHydrochloride

A catalytic amount of platinum on carbon was added to a suspension ofN-phenylmethyl-3-nitro[1,5]naphthyridin-4-amine (5.1 g, 18.2 mmol) intoluene (300 mL). The reaction mixture was hydrogenated on a Parrapparatus under a hydrogen pressure of 50 psi (3.5 Kg/cm²) for 1 hour.The reaction mixture was filtered to remove the catalyst. The filtratewas concentrated under vacuum to a volume of about 200 mL and thenreacted with ethoxyacetyl chloride (2.5 g, 20 mmol). The resultingyellow precipitate was isolated by filtration, suspended in diethylether, and then isolated by filtration to provide 5.8 g ofN-(4-phenylmethylamino[1,5]naphthyridin-3-yl) ethoxyacetamidehydrochloride, m.p. 205–212° C. Analysis: Calculated for C₁₉H₂₀N₄O₂ HCl:% C, 61.21; % H, 5.68; % N, 15.03; Found: % C, 60.90; % H, 5.38; % N,15.38.

EXAMPLE 68 Compound of Formula XXXIII2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine

N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamidehydrochloride (5.8 g, 15.5 mmol) was combined with a 7% solution ofammonia in methanol (100 mL), placed in a sealed Parr vessel and thenheated at 150° C. for 6 hours. The reaction mixture was concentratedunder vacuum. The residue was partitioned between water anddichloromethane. The dichloromethane layer was separated, washed withwater, dried over magnesium sulfate and then concentrated under vacuum.The residue was recrystallized from methyl acetate to provide 4.3 g of2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine, m.p.118–119° C. Analysis: Calculated for C₁₉H₁₈N₄O: % C, 71.68; % H, 5.70; %N, 17.60; Found: % C, 71.44; % H, 5.60; % N, 17.66.

EXAMPLE 69 Compound of Formula XXXIV2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3 portions to asolution of2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine (3.9g, 12.2 mmol) in chloroform (100 mL) in a flask covered with aluminumfoil. The reaction mixture was stirred at ambient temperature overnight;and then it was washed twice with dilute aqueous sodium bicarbonate andonce with brine. The chloroform layer was divided into two portions. Oneportion was used in the example below. The second portion wasconcentrated under vacuum. The residue was recrystallized from isopropylalcohol to provide2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a solid, m.p. 187.5–189° C. Analysis: Calculated for C₁₉H₁₈N₄O₂+¼H₂O:% C, 67.52; % H, 5.49; % N, 16.58; Found: % C, 67.56; % H, 5.36; % N,16.77.

EXAMPLE 70 Compound of Formula I2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Ammonium hydroxide (20 mL) was added to the chloroform solution of2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxidefrom the example above. Tosyl chloride was slowly added. Thin layerchromatography indicated that the reaction was proceeding slowly.Additional tosyl chloride was added twice. After thin layerchromatography indicated that the reaction was complete, the layers wereseparated. The organic layer was washed with dilute aqueous sodiumcarbonate, dried over magnesium sulfate and then concentrated undervacuum. The residue was covered with methyl acetate (10 mL), hexane (5mL) was added and the mixture was allowed to stand overnight. Theresulting crystalline solid was isolated by filtration to provide2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,m.p. 173–174° C. Analysis: Calculated for C₁₉H₁₉N₅O: % C, 68.45; % H,5.74; % N, 21.01; Found: % C, 68.35; % H, 5.83; % N, 21.27.

EXAMPLE 71 Compound of Formula XXXIN⁴-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine

Part A

Phosphorus oxychloride (3.4 mL, 30 mmol) was added to chilled (ice bath)N,N-dimethylformamide (15 mL). The resulting solution was added dropwiseto a solution of 3-nitro[1,5]naphthyridin-4-ol (5.73 g, 30 mmol) inN,N-dimethylformamide (35 mL). The reaction mixture was maintained atambient temperature for 5 hours and then it was poured onto ice. Theresulting yellow precipitate was isolated by filtration and thenpartitioned between dichloromethane (200 mL) and water (150 mL). Theorganic layer was separated, dried over magnesium sulfate, filtered, andthen concentrated under vacuum to provide 4.2 g of crude4-chloro-3-nitro[1,5]naphthyridine.

Part B

4-Chloro-3-nitro[1,5]naphthyridine (4.1 g), dichloromethane (150 mL),triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3 mL,23.8 mmol) were combined. The reaction mixture was maintained at ambienttemperature overnight and then quenched with water (100 mL). The phaseswere separated. The aqueous phase was extracted with dichloromethane(100 mL). The organic phases were combined, dried over magnesiumsulfate, filtered and then concentrated under vacuum to provide a yellowoil. The oil was purified by flash chromatography (silica gel elutingwith 1:1 ethyl acetate:hexanes) to provide 4.8 g ofN⁴-(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellowpowder, m.p. 62.5–63.5° C. Analysis: Calculated for C₁₄H₁₈N₄O₃: % C,57.92; % H, 6.25; % N, 19.30; Found: % C, 57.96; % H, 6.19; % N, 19.51.¹H NMR (300 MHz, CDCl₃) δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78(m, 1H), 8.21 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57(broad s, 2H), 3.65–3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d, J=6.0Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc'd for C₁₄H₁₈N₄O₃).

EXAMPLE 72 Compound of Formula XXXIIN⁴-(3-Isopropoxypropyl)[1,5]naphthyridine-3,4-diamine

N⁴-3-nitro[1,5]naphthyridin-4-amine (4.2 g, 14.5 mmol), platinum oncarbon (1.1 g of 5%), and ethyl acetate (100 mL) were placed in ahydrogenation flask. The mixture was shaken under a hydrogen pressure of50 psi (3.5 Kg/cm²) for 2.5 hours. The reaction mixture was filtered andthe catalyst was washed with ethyl acetate. The filtrate was dried overmagnesium sulfate, filtered and then concentrated under vacuum toprovide 3.6 g of N⁴-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamineas a bright yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 8.70 (dd, J=4.1,1.6Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J=8.4,1.6 Hz, 1H), 7.37 (dd, J=8.4,4.1Hz, 1H), 5.99 (broad s, 1H), 3.98 (broad s, 2H),3.63–3.55 (m, 5H), 1.87(pentet, J=6.2 Hz, 2H), 1.17 (d, J=6.1 Hz, 6H); MS (EI): m/e 260.1630(260.1637 calc'd for C₁₄H₂₀N₄O).

EXAMPLE 73 Compound of Formula XXXIII2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

Part A

Valeryl chloride (1.53 mL, 12.9 mmol) was added dropwise over a 15minute period to a chilled (ice bath) solution ofN⁴-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine (3.2 g, 12.3 mmol)in dichloromethane (40 mL). The cooling bath was removed and thereaction mixture was maintained at ambient temperature for 1 hour. Thesolvent was removed under vacuum to provide a dark tan solid.

Part B

The material from Part A and a 7.5% solution of ammonia in methanol (100mL) were placed in a pressure vessel. The vessel was sealed and thenheated at 150° C. for 6 hours. After the mixture was cooled to ambienttemperature it was concentrated under vacuum. The residue waspartitioned between dichloromethane (150 mL) and water (150 mL). Thefractions were separated and the aqueous fraction was extracted withdichloromethane (100 mL). The organic fractions were combined, driedover magnesium sulfate, filtered and then concentrated under vacuum toprovide a brown oil. The oil was purified by flash chromatography(silica gel eluting with ethyl acetate) to provide 3.1 g of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as acolorless oil. ¹H NMR (300 MHz, CDCl₃: δ 9.32 (s, 1H), 8.90 (dd,J=4.3,1.7 Hz, 1H), 8.49 (dd, J=8.5,1.7 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz,1H), 4.94 (t, J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, 1H), 3,44 (t; J=5.7Hz, 2H), 3.05 (t, J=7.9 Hz, 2H), 2.29–2.20 (m, 2H), 2.01–1.90 (m, 2H),1.60–1.48 (m, 2H), 1.15 (d, J=6.1 Hz, 6H), 1.03 (t, J=7.3 Hz, 3H); MS(EI): m/e 326.2104 (326.2106 calc'd for C₁₉H₂₆N₄O).

EXAMPLE 74 Compound of Formula XXXIV2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (1.2 g of 57–86%) was added in four portionsover a period of 20 minutes to2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.4g, 4.3 mmol) in chloroform (20 mL). The reaction mixture was maintainedat ambient temperature for 2 hours and then it was washed with saturatedsodium bicarbonate (2×15 mL) and water (20 mL). The organic fraction wasdried over magnesium sulfate, filtered and then concentrated undervacuum to provide a yellow oil. The oil was purified by columnchromatography (silica gel eluting with 95:5 ethyl acetate:methanol) toprovide 0.95 g of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow solid, m.p. 92.0–93.0° C. Analysis: Calculated forC₁₉H₂₆N₄O₂: % C, 66.64; % H, 7.65; % N, 16.36; Found: % C, 66.18; % H,7.39; % N, 16.26. ¹H NMR (300 MHz, CDCl₃): δ 9.24 (dd, J=8.8,1.6 Hz,1H), 9.05 (s, 1H), 8.98 (dd, J=4.3,1.6 Hz, 1H), 7.65 (dd, J=8.8,4.3 Hz,1H), 4.89 (t, J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, 1H), 3.44 (t, J=5.7Hz, 2H), 3.02 (t, J=7.9 Hz, 2H), 2.27–2.18 (m, 2H), 1.97–1.87 (m, 2H),1.59–1.47 (m, 2H), 1.15 (d, J=6.1 Hz, 6H), 1.02 (t, J=7.3 Hz, 3H).

EXAMPLE 75 Compound of Formula I2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine

Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.42 mL, 3.5mmol) was added dropwise to a solution of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(0.8 g, 2.3 mmol) in dichloromethane (25 mL). The reaction mixture wasmaintained at ambient temperature for 2 hours and then concentratedunder vacuum to provide a yellow oil. The oil was dissolved in methanol(15 mL) and then sodium methoxide (0.8 mL of 25% in methanol, 3.5 mmol)was slowly added. The reaction was maintained at ambient temperatureovernight. The resulting precipitate was isolated by filtration and thenrecrystallized from methyl acetate to provide 0.47 g of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amineas a white crystalline solid, m.p. 174–175° C. Analysis: Calculated forC₁₉H₂₇N₅O: % C, 66.83; % H, 7.97; % N, 20.51; Found: % C, 66.70; % H,7.81; % N, 20.75. ¹H NMR (300 MHz, CDCl₃): δ 8.50 (dd, J=4.3,1.5 Hz,1H), 7.90 (dd, J=8.4,1.5 Hz, 1H), 7.42 (dd, J=8.4,4.3 Hz, 1H), 6.75 (s,2H), 4.77 (t, J=6.8 Hz, 2H), 3.50 (pentet, J=6.1 Hz, 1H), 3.35 (m, 2H),2.95 (t, J=7.8 Hz, 2H), 2.13–2.04 (m, 2H), 1.86–1.76 (m, 2H), 1.52–1.40(m, 2H), 1.05 (d, J=6.1 Hz, 6H), 0.97 (t, J=7.3 Hz, 3H).

EXAMPLE 76 Compound of Formula XXXIN⁴-(3-Butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine

Under a nitrogen atmosphere, 3-butoxypropylamine (4.0 mL, 26 mmol) wasadded dropwise over a period of 10 minutes to a solution of4-chloro-3-nitro[1,5]naphthyridine (4.6 g, 22 mmol) and triethylamine(4.6 mL, 33 mmol) in dichloromethane (150 mL). The reaction mixture wasmaintained at ambient temperature overnight. Water (100 mL) was addedand the phases were separated. The aqueous phase was extracted withdichloromethane (100 mL). The organic fractions were combined, driedover magnesium sulfate, filtered and then concentrated under vacuum toprovide a yellow oil. The oil was purified by flash chromatography(silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 5.3 g ofN⁴-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a colorless oil.¹H NMR (300 MHz, CDCl₃): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78(m, 1H), 8.22 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57(broad s, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.10–2.03(m, 2H), 1.65–1.55 (m, 2H), 1.44–1.32 (m, 2H), 0.92 (t, J=7.3 Hz, 3H);MS (EI): m/e 304.1535 (304.1535 calc'd for C₁₅H₂₀N₄O₃).

EXAMPLE 77 Compound of Formula XXXII N⁴-(3-Butoxypropyl)[1,5]naphthyridine-3,4-diamine

Using the method of Example 72,N⁴-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.9 g, 16 mmol)was reduced to provide 4.3 g ofN⁴-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellowoil. Analysis: Calculated for C₁₅H₂₂N₄O: % C, 65.67; % H, 8.08; % N,20.42; Found: % C, 65.48; % H, 8.07; % N, 20.41. ¹H NMR (300 MHz, CDCl₃:δ 8.70 (dd, J=4.1,1.6 Hz, 1H), 8.39 (s, 1H), 8.18 (dd, J=8.4,1.6 Hz,1H), 7.37 (dd, J=8.4,4.1 Hz, 1H), 5.97 (broad s, 1H), 3.96 (broad s,2H), 3.63–3.56 (m, 4H), 3.44 (t, J=6.7 Hz, 2H), 1.89 (pentet, J=6.2 Hz,2H), 1.63–1.53 (m, 2H), 1.44–1.32 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); MS(EI): m/e 274.1799 (274.1793 calc'd for C₁₅H₂₂N₄O).

EXAMPLE 78 Compound of Formula XXXIII1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine

Using the general method of Example 73 Part A and Part B,N⁴-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) wasreacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resultingamide intermediate was cyclized to provide 2.9 g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as acolorless oil. A small portion was purified by flash chromatography(silica gel eluting with ethyl acetate) to provide a pure sample as awhite powder, m.p. 56.5–57.5° C. Analysis: Calculated for C₂₀H₂₈N₄O: %C, 70.56; % H, 8.29; % N, 16.46; Found: % C, 70.48; % H, 8.25; % N,16.61. ¹H NMR (300 MHz, CDCl₃): δ 9.32 (s, 1H), 8.90 (dd, J=4.3,1.6 Hz,1H), 8.49 (dd, J=8.5,1.6 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, 1H), 4.94 (t,J=7.0 Hz, 2H), 3.45–3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26 (pentet,J=6.1 Hz, 2H), 2.01–1.91 (m, 2H), 1.62–1.48 (m, 4H), 1.45–1.33 (m, 2H),1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

EXAMPLE 79 Compound of Formula XXXIV1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

Using the general method of Example 74,1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine (2.2 g,6.47 mmol) was oxidized to provide 1.6 g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow powder, m.p. 126.5–127.5° C. Analysis: Calculated forC₂₀H₂₈N₄O₂: % C, 67.39; % H, 7.92; % N, 15.72; Found: % C, 67.13; % H,7.69; % N, 15.82. ¹H NMR (300 MHz, CDCl₃): δ 9.22 (dd, J=8.8,1.5 Hz,1H), 9.04 (s, 1H), 8.99 (dd, J=4.3,1.5 Hz, 1H), 7.65 (dd, J=8.8,4.3 Hz,1H), 4.89 (t, J=7.0 Hz, 2H), 3.46–3.39 (m, 4H), 3.01 (t, J=7.9 Hz, 2H),2.28–2.20 (m, 2H), 1.97–1.87 (m, 2H), 1.62–1.46 (m, 4H), 1.45–1.33 (m,2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

EXAMPLE 80 Compound of Formula I1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Using the general method of Example 75,1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.2 g, 3.4 mmol) was reacted with trichloroacetyl isocyanate (0.6 mL,5.0 mmol) and the resulting intermediate was hydrolyzed to provide 0.86g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa white powder, m.p. 101.0–101.5° C. Analysis: Calculated for C₂₀H₂₉N₅O:% C, 67.58; % H, 8.22; % N, 19.70; Found: % C, 67.55; % H, 7.96; % N,20.10. ¹H NMR (300 MHz, DMSO): δ 8.50 (dd, J=4.4,1.5 Hz, 1H), 7.91 (dd,J=8.4,1.6 Hz, 1H), 7.42 (dd, J=8.4,4.4 Hz, 1H), 6.77 (s, 2H), 4.78 (t,J=6.9 Hz, 2H), 3.38–3.30 (m, 4H), 2.93 (t, J=7.8 Hz, 2), 2.11 (pentet,J=6.1 Hz, 2H), 1.82 (pentet, J=7.6 Hz, 2H), 1.51–1.39 (m, 4H), 1.37–1.25(m, 2H), 0.96 (t, J=7.3 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 81 Compound of Formula XXXIN⁴-(2-Phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine

Using the general method of Example 76,4-chloro-3-nitro[1,5]naphthyridine (5.0 g, 24 mmol) was reacted with2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g ofN⁴-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid,m.p. 107–108° C. Analysis: Calculated for C₁₆H₁₄N₄O₃: % C, 61.93; % H,4.55; % N, 18.05; Found: % C, 61.99; % H, 4.58; % N, 18.42. ¹H NMR (300MHz, DMSO): δ 10.25 (broad s, 1H), 9.39 (broad s, 1H), 8.81 (dd,J=4.1,1.7 Hz, 1H), 8.25 (dd, J=8.5,1.7 Hz, 1H), 7.67 (dd, J=8.5,4.1 Hz,1H), 7.34–7.26 (m, 2H), 7.01–6.96 (m, 3H), 4.89 (broad s, 2H), 4.35 (t,J=5.1 Hz, 2H); MS (EI): m/e 310.1065 (310.1065 calc'd for C₁₆H₁₄N₄O₃).

EXAMPLE 82 Compound of Formula XXXII N⁴— (2-Phenoxyethyl)[1,5]naphthyridine-3,4-diamine

Using the general method of Example 77,N⁴-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine (5.4 g, 17.4 mmol)was reduced to provide 4.6 g ofN⁴-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine as a bright yellowoil. ¹H NMR (300 MHz, DMSO): δ 8.68 (dd, J=4.1,1.7 Hz, 1H), 8.40 (s,1H), 8.10 (dd, J=8.4,1.7 Hz, 1H), 7.39 (dd, J=8.4,4.1 Hz, 1H), 7.28–7.22(m, 2H), 6.94–6.90 (m, 3H), 6.12 (t, J=7.0 Hz, 1H), 5.15 (s, 2H), 4.13(t, J=5.5 Hz, 2H), 3.93–3.87 (m, 2H); MS (CI): m/e 281 (M+H).

EXAMPLE 83 Compound of Formula XXXIII2-(2-Butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl Phenyl Ether

Using the general method of Example 73 Part A and Part B,N⁴-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) wasreacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resultingamide intermediate was cyclized to provide 4.0 g of2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether asa white solid, m.p. 150–150.5° C. Analysis: Calculated for C₂₁H₂₂N₄O: %C, 72.81; % H, 6.40; % N, 16.17; Found: % C, 72.78; % H, 6.40; % N,16.31. ¹H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3,1.7 Hz,1H), 8.52 (dd, J=8.4,1.7 Hz, 1H), 7.74 (dd, J=8.4,4.3 Hz, 1H), 7.25–7.20(m, 2H), 6.91–6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz,2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55–1.43 (m,2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc'd forC₂₁H₂₂N₄O).

EXAMPLE 84 Compound of Formula XXXIV2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

Using the general method of Example 74,2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether(0.6 g, 1.7 mmol) was oxidized to provide 0.44 g of2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow powder. ¹H NMR (300 MHz, CDCl₃): δ 9.10–9.03 (m, 3H), 7.81(dd, J=8.7,4.3 Hz, 1H), 7.25–7.20 (m, 2H), 6.92–6.83 (m, 3H), 5.16 (t,J=4.9 Hz, 2H), 4.51 (t, J=4.9 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 1.93–1.83(m, 2H), 1.54–1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (CI): m/e 363(M+H).

EXAMPLE 85 Compound of Formula I2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Using the general method of Example 75,2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(0.38 g, 1.05 mmol) was reacted with trichloroacetyl isocyanate (0.19mL, 1.6 mmol) and the resulting intermediate was hydrolyzed to provide0.23 g of2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa white powder, m.p. 159.0–159.2° C. ¹H NMR (300 MHz, DMSO): δ 8.52 (dd,J=4.4,1.5 Hz, 1H), 7.92 (dd, J=8.4,1.5 Hz, 1H), 7.45 (dd, J=8.4,4.4 Hz,1H), 7.26–7.21 (m, 2H), 6.92–6.86 (m, 3H), 6.79 (s, 2H) 5.13 (t, J=5.2Hz, 2H), 4.48 (t, J=5.2 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 1.91–1.81(pentet, J=7.4 Hz, 2H), 1.52–1.40 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS(EI): m/e 361.1899 (361.1902 calc'd for C₂₁H₂₃N₅O).

EXAMPLE 86 Compound of Formula XXXI 1,1-DimethylethylN-{2-[(3-Nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate

A solution of diisopropylethylamine (13.47 g, 0.10 mole) indichloromethane (25 mL) was added to a solution of5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) indichloromethane (250 mL). A solution of tert-butylN-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL)was slowly added to the reaction mixture. The reaction mixture washeated at reflux overnight. Additional tert-butylN-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture washeated at reflux for an additional 3 hours. The reaction mixture wasallowed to cool to ambient temperature and then it was diluted withadditional dichloromethane, washed with water and with brine, dried, andthen concentrated under vacuum to provide a dark solid. This solid waspurified by flash chromatography (silica gel eluting withdichloromethane) to provide 24.8 g of 1,1-dimethylethylN-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethylcarbamate as a canaryyellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL)and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p.149–151° C. Analysis: Calculated for C₁₅H₁₉N₅O₄: % C, 54.05; % H, 5.75;% N, 21.01; Found: % C, 54.17; % H, 5.73; % N, 20.90.

EXAMPLE 87 Compound of Formula XXXII 1,1-DimethylethylN-{2-[(3-Amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate

1,1-DimethylethylN-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (10 g, 0.03mol), ethyl acetate (800 mL) and platinum on carbon catalyst werecombined in a Parr bottle and then the mixture was hydrogenatedovernight. The reaction mixture was filtered to remove the catalyst. Thefiltrate was concentrated under vacuum to provide 9.1 g of1,1-dimethylethylN-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a yellowsyrup. Analysis: Calculated for C₁₅H₂₁N₅O₂+0.1 CH₃CO₂C₂H₅: % C, 59.25; %H, 7.04; % N, 22.43; Found: % C, 58.96; % H, 6.87; % N, 22.46.

EXAMPLE 88 Compound of Formula XXXIII 1,1-DimethylethylN-[2-(B-butyl-1H-imidazo[4,5-c]1,5]naphthyridin-1-yl)ethyl]carbamate

1,1-DimethylethylN-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate 0.6 g, 2mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL)were combined and heated at reflux for 2 hours. Additional trimethylorthovalerate (1 eq.) was added and the reaction mixture was heated atreflux overnight. Xylene was added and the toluene was distilled off.The reaction was heated at reflux for an additional 8 hours. The bulk ofthe xylene was distilled off leaving a volume of about 5 mL. Thereaction mixture was allowed to cool. The resulting precipitate wasisolated by filtration, washed with heptane and dried to provide 0.35 gof 1,1-dimethylethylN-[2-(2-butyl-1H-imidazo[4,5-c]1,5]naphthyridin-1-yl)ethyl]carbamate asan ivory powder, m.p. 198–199° C. Analysis: Calculated for C₂₀H₂₇N₅O₂: %C, 65.01; % H, 7.36; % N, 18.95; Found: % C, 64.75; % N, 7.57; % N,19.09.

EXAMPLE 89 Compound of Formula XXXIII1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

3-Chloroperbenzoic acid (0.7 g of 57–86%) was dissolved in chloroform(10 mL). One half of this solution was added to a solution of1,1-dimethylethylN-[2-(2-butyl-1H-imidazo[4,5-c]1,5}naphthyridin-1-yl)ethyl]carbamate(1.0 g, 2.7 mmol) in chloroform (10 mL). The reaction mixture wasstirred at ambient temperature for 30 minutes and then the remaininghalf of the chloroperbenzoic acid solution was added dropwise to thereaction mixture. The reaction mixture was stirred at ambienttemperature for a: total of 2.5 hours and then it was diluted withchloroform (50 mL); washed with sodium carbonate, with 10% sodiumhydroxide, with water, and with brine; dried and concentrated undervacuum to provide 1.1 g of a yellow solid. This material wasrecrystallized twice from acetonitrile to provide 1.0 g of1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.Analysis: Calculated for C₂₀H₂₇N₅O₃: % C, 62.32; % H, 7.06; % N, 18.17;Found: % C, 62.03; % H, 6.73; % N, 18.10.

EXAMPLE 90 Compound of Formula I 1,1-DimethylethylN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate

Trichloroacetyl isocyanate (4.8 mL, 40 mmol) was added via a syringe toa solution of1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(10.4 g, 27 mmol) in dichloromethane (75 mL). The reaction mixture wasstirred at ambient temperature for 1 hour. Sodium methoxide (9 mL of 25%sodium methoxide in methanol) was added and the reaction mixture wasstirred at ambient temperature overnight. Thin layer chromatographyindicated that the reaction was not complete so additional sodiummethoxide was added twice with each addition being followed by 2 hoursof stirring at ambient temperature. The reaction mixture was dilutedwith dichloromethane; washed with sodium carbonate, water, and thenbrine; dried and then concentrated under vacuum to provide 10.4 g of ayellow solid. This material was purified by column chromatography(silica gel eluting with dichloromethane) to provide 8.5 g of a solid.This solid was recrystallized from toluene (20 mL) to provide 6.0 g of1,1-dimethylethylN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamateas ivory crystals, m.p. 118–120° C. Analysis: Calculated for C₂₀H₂₈N₆O₂:% C, 62.48; % H, 7.34; % N, 21.85; Found: % C, 62.31; % H, 7.23; % N,22.13. HRMS (EI) calcd for C₂₀H₂₈N₆O₂ (M+) 384.2273, found 384.2273.

EXAMPLE 91 Compound of Formula I2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine

Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethylN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate(5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture wasstirred at ambient temperature for 1 hour. The reaction mixture wasdiluted with dichloromethane and then extracted with 10% hydrochloricacid. The hydrochloric acid extract was washed twice withdichloromethane and then it was made basic with ammonium hydroxide. Theresulting precipitate was isolated by filtration and dried to provide3.7 g of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamineas a white powder, m.p. 175–176° C. Analysis: Calculated for C₁₅H₂₀N₆: %C, 63.36; % H, 7.09; % N, 29.55; Found: % C, 62.98; % H, 6.92; % N,29.89. HRMS (EI) calcd for C₁₅H₂₀N₆ (M+) 284.1749, found 284,1748.

EXAMPLE 92 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamide

Under a nitrogen atmosphere, acetyl chloride (50 μL, 0.7 mmole) indichloromethane (25 mL) was added dropwise to a cooled (ice bath)solution of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition wascomplete, the reaction mixture was allowed to warm to ambienttemperature. After 30 minutes thin layer chromatography indicated thatthe reaction was complete. The reaction mixture was washed with 10%sodium hydroxide, water and brine; dried; and concentrated under vacuumto provide 0.25 g of crude product. This material was purified by columnchromatography (silica gel eluting with dichloromethane) to provide 0.2g of a solid. This solid was recrystallized from acetonitrile (30 mL) toprovide 0.18 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamideas a white powder, m.p. 228–230° C. Analysis: Calculated for C₁₇H₂₂N₆O:% C, 62.56; % H, 6.79; % N, 25.75; Found: % C, 62.50; % H, 6.59; % N,26.04. HRMS (EI) calcd for C₂₂H₂₆N₆O₂ (M+) 326.1855, found 326.1846.

EXAMPLE 93 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide

Using the general method of Example 92, crotonyl chloride (68 μL, 0.7mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) to provide 0.2 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamideas a white powder, m.p. 198–200° C. Analysis: Calculated for C₁₉H₂₄N₆O:% C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N,23.99. HRMS (EI) calcd for C₁₉H₂₄N₆O (M+) 352.2011 found 352.1996.

EXAMPLE 94 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide

Using the general method of Example 92, cyclohexanecarbonyl chloride (94μL, 0.7 mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) to provide 0.2 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamideas a white powder, m.p. 188–190° C. Analysis: Calculated for C₂₂H₃₀N₆O:% C, 66.98; % H, 7.66; % N, 21.30; Found: % C, 66.72; % H, 7.57; % N,21.48. HRMS (EI) calcd for C₂₂H₃₀N₆O (M+) 394.2481 found 394.2475.

EXAMPLE 95 Compound of Formula IN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide

Using the general method of Example 92, 3,5-di-(1,1dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reactedwith2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamideas a white powder, m.p. 248–250° C. Analysis: Calculated for C₃₀H₄₀N₆O₂:% C, 69.74; % H, 7.80; % N, 16.27; Found: % C, 69.65% H, 7.69; % N,16.42. HRMS (EI) calcd for C₃₀H₄₀N₆O₂ (M+) 516.3212 found 516.3226.

EXAMPLE 96 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3-phenylpropanamideHydrochloride

Using the general method of Example 92, hydrocinnamoyl chloride (0.1 g,0.7 mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol). After one hour the reaction mixture was poureddirectly onto a silica gel column and eluted with dichloromethane atfirst, then 15% methanol/dichloromethane to provide 0.2 g of a solid.This solid was recrystallized from toluene to provide 0.2 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3-phenylpropanamidehydrochloride as a white powder, m.p. 183–185° C. Analysis: Calculatedfor C₂₄H₂₈N₆O HCl: % C, 63.64; % H, 6.45; % N, 18.55; Found: % C, 63.68;% H, 6.43; % N, 18.55.

EXAMPLE 97 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamide

A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (0.23 g,1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to asolution of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) in anhydrous dichloromethane (100 mL). The reactionmixture was stirred at ambient temperature for 30 minutes and then asolution of 1-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimidehydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL)was added dropwise. The reaction mixture was stirred at ambienttemperature overnight and then filtered to remove solids. The filtratewas washed twice with 10% sodium hydroxide and then with brine, dried,and then concentrated under vacuum to provide 0.3 g of crude product.This material was purified by column chromatography (silica gel elutingwith dichloromethane) followed by recrystallization from acetonitrile toprovide 0.1 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamideas a white powder, m.p. 153–154° C. Analysis: Calculated for C₂₀H₂₄N₆O₃:% C, 60.59; % H, 6.10; % N, 21.19; Found: % C, 60.34; % H, 6.14; % N,21.13. HRMS (EI) calcd for C₂₀H₂₄N₆O₃ (M+) 396.1909 found 396.1905.

EXAMPLE 98 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamide

Using the general method of Example 97 3-hydroxyphenyl acetic acid (0.26g, 1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.13 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamideas a white powder, m.p. 208–210° C. Analysis: Calculated for C₂₃H₂₆N₆O₂:% C, 66.01; % H, 6.26; % N, 20.08; Found: % C, 65.63; % H, 6.11; % N,20.30. HRMS (EI) calcd for C₂₃H₂₆N₆O₂ (M+) 418.2117 found 418.2109.

EXAMPLE 99 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide

Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g,1.7 mmole) was reacted with2-(4-amino-2-butyl-1-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.15 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamideas a white powder, m.p. 258–260° C. Analysis: Calculated forC₂₁H₂₃N₇O₂+½CH₃CN: % C, 62.03; % H, 5.80; % N, 24.66; Found: % C, 61.87;% H, 5.70; % N, 24.60.

EXAMPLE 100 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]3,7-dimethyl-6-octenamide

Using the general method of Example 97 citronellic acid (0.3 g, 1.7mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamideas a white whispy solid, m.p. 163–164° C. Analysis: Calculated forC₂₅H₃₆N₆O: % C, 68.77; % H, 8.31; % N, 19.25; Found: % C, 68.84; % H,8.14; % N, 19.58. HRMS (EI) calcd for C₂₅H₃₆N₆O (M+) 436.2950 found436.2952.

EXAMPLE 101 Compound of Formula I 1,1-DimethylethylN-[1-({[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate

Using the general method of Example 97N-t-BOC-L-leucine (0.41 g, 1.7mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g of 1,1-dimethylethylN-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamateas a white solid, m.p. 184–185° C. HRMS (EI) calcd for C₂₆H₃₉N₇O₃ (M+)497.3114 found 497.3093.

EXAMPLE 102 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]2-amino-4-methylpentanamide

1,1-DimethylethylN-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate(0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) andheated on a steam bath for 30 minutes. The reaction mixture was allowedto cool and then it was made basic with 10% sodium hydroxide. Theresulting precipitate was isolated by filtration and dried to provide0.15 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentamideas a white solid, m.p. 60–65° C. Analysis: Calculated for C₂₁H₃₁N₇O: %C, 63.27; % H, 7.86; % N, 24.66; Found: % C, 62.27; % H, 7.67; % N,24.77. HRMS (EI) calcd for C₂₁H₃₁N₇O (M+) 397.2590 found 397.2582.

EXAMPLE 103 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide

Using the general method of Example 973,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reactedwith2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.23 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamideas a white powder, m.p. 188–189° C. Analysis: Calculated for C₂₁H₂₅N₇O₂:% C, 61.90; % H, 6.18; % N, 24.06; Found: % C, 61.92; % H, 6.15; % N,24.28. HRMS (EI) calcd for C₂₁H₂₅N₇O₂ (M+) 407.2069 found 407.2068.

EXAMPLE 104 Compound of Formula IIN¹-[2-(4-Amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide

A solution ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide(0.1 g, 0.19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide(0.1 g) were combined and hydrogenated overnight on a Parr apparatus.The reaction mixture was filtered to remove the catalyst. The filtratewas concentrated under vacuum. The residue was dissolved indichloromethane. The dichloromethane solution was washed twice with 10%sodium hydroxide and with brine, dried and then concentrated undervacuum to provide crude product. This material was purified bychromatography eluting with 10% methanol in dichloromethane. Theresulting oil was triturated with acetonitrile to provide 0.05 g ofN¹-[2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamideas a white powder, m.p. 208–210° C. Analysis: Calculated forC₃₀H₄₄N₆O₂+0.1 CF₃CO₂H: % C, 68.17; % H, 8.35; % N, 15.79; Found: % C,68.48; % H, 8.29; % N, 16.08.

EXAMPLE 105 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentamide

4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g), 5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentanoicacid (0.18 g) and dichloromethane (100 mL) were combined and stirred atambient temperature for 30 minutes.1-[3-(Dimethylamino)propy]-3-ethylcarbodiimide (0.12 g) was added andthe reaction mixture was stirred at ambient temperature for 2 hours. Thereaction was filtered through a column of silica gel and eluted with 10%methanol in dichloromethane to provide 0.2 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentamide,m.p. 153.5–155° C. Analysis: Calculated for C₂₉H₃₈N₁₀O₃: % C, 60.61; %H, 6.66; % N, 24.37; Found: % C, 60.65; % H, 6.66; % N, 24.32.

EXAMPLE 106 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-morpholinonicotinamide

Using the general method of Example 105 6-morpholinonicotinic acid (0.12g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-morpholinonicotinamideas a white solid, m.p. 95–100° C. Calculated for C₂₇H₃₄N₈O₂+½H₂O: % C,63.39; % H, 6.90: % N, 21.90; Found: % C, 63.69; % H, 6.95; % N, 21.52.

EXAMPLE 107 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-quinolinecarboxamide

Using the general method of Example 105 6-quinolinecarboxylic acid (0.11g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-quinolinecarboxamideas a white solid, m.p. 190–191° C. Analysis: Calculated for C₂₇H₂₉N₇O+1/4H₂O: % C, 68.70; % H, 6.30; % N, 20.77; Found: % C, 68.54; % H, 6.21;% N, 20.93.

EXAMPLE 108 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamide

Using the general method of Example 1052-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetic acid (0.12g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provide 0.06 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamideas a solid, m.p. 242–244° C.

EXAMPLE 109 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide

Using the general method of Example 105 (2-pyrimidinylthio)acetic acid(0.11 g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamideas a white solid, m.p. 156–160° C. (dec.).

EXAMPLE 110 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamide

Using the general method of Example 105 (4-pyridylthio)acetic acid (0.11g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provide 0.1 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamideas a solid, m.p. 127.5–129° C.

EXAMPLE 111 Compound of Formula I4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine

Part A

Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solution of1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1mmol) in toluene (150 mL). The reaction was heated at reflux overnightwith ethanol being collected in a Dean Stark trap. The reaction mixturewas heated at reflux for an additional 6 hours and thenp-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction wasrefluxed overnight. A dark orange/brown oil had formed. The toluenesupernatant was decanted off and concentrated under vacuum to provide1.1 g of 1,1-dimethylethylN-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The oilwas identified as4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine. This materialwas reacted with 1,1-dimethylethyl-dicarbonate to provide an additional1 g of 1,1-dimethylethylN-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The twolots were combined and carried on to the next step.

Part B

3-Chloroperbenzoic acid (1.86 g of 60%) was added in small portions to asolution of the material from Part A in chloroform (25 mL). The reactionwas maintained at ambient temperature overnight and then it was dilutedwith 5% sodium carbonate solution. The layers were separated. Theorganic layer was concentrated under vacuum. The residue was slurriedwith hot methyl acetate, cooled and then filtered to provide 2.0 g of 1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.

Part C

Tosyl chloride (0.64 g, 3.37 mmol) was slowly added in small portions toa solution of the material from Part B (1.2 g, 3.37 mmol) indichloromethane (20 mL). After 4 hours an additional 100 mg of tosylchloride was added to drive the reaction to completion. The reaction wasquenched with concentrated ammonium hydroxide (5 mL) and water (10 mL)and stirred at ambient temperature over the weekend. The layers wereseparated. The organic layer was concentrated under vacuum to provide atan solid. This solid was slurried in hot methyl acetate, cooled and thefiltered to provide 0.9 g of 1,1-dimethylethylN-[4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate.

Part D

A mixture of the material from Part C and 1 N hydrochloric acid (25 mL)was heated at reflux until thin layer chromatography indicated that thereaction was complete. The mixture was adjusted to pH 14 with 6 N sodiumhydroxide. The resulting precipitate was isolated by filtration toprovide 0.2 g of4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine as a paleyellow solid, m.p. 161–163° C. Mass spec (M+1)=257.09.

EXAMPLE 112 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]4-{[2-(dimethylamino)ethoxy](phenyl)methyl}benzamide

Part A

Under a nitrogen atmosphere phenyl magnesium bromide (39 mL of 3 M inether) was added via a syringe over a period of 30 minutes to a solutionof methyl 4-formylbenzoate (19.2 g, 117 mmol). The mixture was allowedto stir for an additional 10 minutes and then it was quenched by theaddition of 1 M hydrochloric acid (125 mL). The reaction mixture wasextracted with diethyl ether (2×200 mL). The combined extracts werewashed with brine, dried over magnesium sulfate, filtered and thenconcentrated under vacuum to provide a yellow oil. This material waspurified by flash chromatography (silica gel eluting with 6:1hexanes:ethyl acetate) to provide 6.9 g of methyl4-(<(-hydroxybenzyl)benzoate as a clear oil.

Under a nitrogen atmosphere a suspension of p-toluenesulfonic acidmonohydrate (10.7 g, 56 mmol) in toluene (70 mL) was heated at reflux.Water (˜1 mL) was collected in a Dean Stark trap. The heating mantle wasremoved. To the warm mixture was added a solution of methyl4-(<-hydroxybenzyl)benzoate (3.47 g, 14 mmol) andN,N-dimethylethanolamine (2.9 mL, 28 mmol) in a minimal amount oftoluene. The mixture was heated at reflux for 20 minutes and thenallowed to cool to ambient temperature. The reaction mixture waspartitioned between diethyl ether and saturated aqueous sodiumbicarbonate (the aqueous layer was basic). The aqueous layer wasextracted with an additional 100 mL of diethyl ether. The combinedorganic layers were dried and then concentrated under vacuum. Theresidue was purified by flash chromatography (silica gel eluting with5%, then 10% methanol in dichloromethane) to provide 2.49 g of methyl4-[<-(2-N,N-dimethylaminoethoxy)benzyl]benzoate as a colorless oil.

1 N Sodium hydroxide (2.54 mL) was added to a solution of methyl4-[<-(2-N,N-dimethylaminoethoxy)benzyl]benzoate (0.53 g, 1.7 mmol) inmethanol (10 mL). The solution was heated at reflux for 1 hour, allowedto cool to ambient temperature and then neutralized (pH 5–6) with 1 Nhydrochloric acid (2.54 mL). The mixture was concentrated under vacuum(bath at 45° C.). The resulting residue was extracted into a mixture ofdichloromethane (15 mL) and methanol (3 mL). The extract was filteredand the filtrate was concentrated under vacuum to provide a viscousresidue. Trituration with several portions of diethyl ether provided0.39 g of 4-[<-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid as a whitepowder.

Part B

4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.130 g, 0.4175 mmol) and4-[<-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid (0.125 g, 0.4175mmol) were combined in dichloromethane (150 mL) and stirred at ambienttemperature until a clear solution was obtained.1-[3-(Dimethylamino)propy]-3-ethylcarbodiimide hydrochloride (0.088 g,0.46 mmol) was added and the reaction was maintained at ambienttemperature for 2 days. The volume of dichloromethane was reduced andthe concentrate was purified by flash chromatography (silica gel elutingwith 10% methanol in dichloromethane) to provide 0.085 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-{[2-(dimethylamino)ethoxy](phenyl)methyl}benzamideas a solid, m.p. 105–108° C. Mass spec (M+1)=594.30.

EXAMPLE 113 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamide

Using the general method of Example 112 Part B, 4-benzoylbenzoic acid(72 mg, 0.32 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(100 mg, 0.32 mmol) to provide 30 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamideas a white solid. Mass-spec (M+1=521.31).

EXAMPLE 114 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyrimidinyl)acetamide

Using the general method of Example 112 Part B, thymine-1-acetic acid(130 mg, 0.70 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(200 mg, 0.70 mmol) to provide 68 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyrimidinyl)acetamideas a white solid, m.p. 241–242° C. Mass-spec (M+1=451.24).

EXAMPLE 115 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-(5-methyl-2-oxo-4-imidazolidinyl)hexamide

Using the general method of Example 112 Part B, D-desthiobiotin (151 mg,0.70 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(200 mg, 0.70 mmol) to provide 231 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-(5-methyl-2-oxo-4-imidazolidinyl)hexamideas a white solid, m.p. 184–186° C. Mass spec (M+1=481.35).

EXAMPLE 116 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]methanesulfonamide

Using the method of Examples below,4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(14 mg, 50 μmol) was reacted with methanesulfonyl chloride (4 μL, 50μmol) to provide 5.3 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]methanesulfonamide.1H NMR (500 MHz d6-DMSO)™=8.49 (dd, J=4.3; 1.5 Hz, 1H), 7.92 (dd, J=8.0;1.5 Hz, 1H), 7.44 (dd, J=8.0; 4.3 Hz, 1H), 7.30 (t, J=6 Hz, 1H), 6.76(s, 2H), 4.77 (t, J=6 Hz, 2H), 3.50 (q, J=6 Hz, 2H), 2.98 (t, J=7 Hz,2H), 2.85 (s, 3H), 1.82 (quintet, J=7 Hz, 2H), 1.46 (m, 2H), 0.96 (t,J=7 Hz, 3H). Mass spec by APCI (+/−) plug injection gave desired MW.

EXAMPLE 117 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]benzenesulfonamide

Using the method of Examples 118–152 below,4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(14 mg, 50 μmol) was reacted with benzenesulfonyl chloride (6 μL, 50μmol) to provide 10.9 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]benzenesulfonamide.¹H NMR (500 MHz, d6-DMSO)™=8.43 (dd, J=4.4; 1.5 Hz, 1H), 7.94 (t, J=6Hz, 1H), 7.89 (dd, J=8.4; 1.5 Hz, 1H), 7.68 (d, J=8 Hz, 2H), 7.58 (t,J=8 Hz, 1H), 7.50 (t, J=8 Hz, 2H), 7.41 (dd, J=8.4; 4.4 Hz, 1H), 4.72(t, J=6 Hz, 2H), 3.34 (m, 2 I), 2.97 (t, J=7 Hz, 2H), 1.81 (quintet, J=7Hz, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.97 (t, J=7 Hz, 3H). Mass spec byAPCI (+/−) plug injection gave desired MW.

EXAMPLES 118–152 Compounds of Formula I

The compounds of Examples 118–152 shown in the table below were preparedaccording to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(50 μmol) was dissolved in dichloromethane (5 mL) in a screw-capped testtube and the solution was cooled in an ice-water bath. An acid chloride(50 μmol) of the formula R_(A)COCl was added as a solution in 100 μL ofdichloromethane (Acid chlorides that are solids were either dissolved orsuspended in ˜400 μL of dichloromethane and then added). The mixture wasvortexed for 15 seconds to 1 minute, becoming cloudy, and then ˜80 mg ofan aminomethyl polystyrene resin (0.62 meq/g, 100–200 mesh, 1%crosslink, Bachem #D-2100, lot # FM507) was added, and the mixture wasvortexed for another 30 seconds. The mixture was applied to a shortcolumn (3×1 cm) of silica gel conditioned with dichloromethane. Theproduct was eluted with 10:1 dichloromethane:methanol, collecting ˜2 mLfractions. Thin layer chromatography of the fractions was performed, andfractions with the product spot were pooled and stripped to dryness in aSavant SpeedVac. Purity was checked by reversed phase-HPLC (HPLCconditions refer to using a Hewlett Packard HP 1090 system fitted with aC18 Rainin Microsorb MV column, 4.6×50 mm, particle size=3 microns, poresize=100 Angstroms. Gradient elution: linear gradient from 100% water+0.1% trifluoroacetic acid to 100% acetonitrile +0.1% trifluoroaceticacid over 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm).APCI-mass spectral data confirmed presence of the expected molecularion, and proton nmr data supported the expected structure.

Example # R_(A) Fragment ¹H NMR(500MHz, solvent indicated) 118

(d₆-DMSO)δ 8.51(dd, J=4.4, 1.5Hz, 1H),7.91(dd, J=8.3, 1.5Hz, 1H),7.46(t, J=6Hz,1H), 7.44(dd, J=8.3, 4.4Hz, 1H), 6.73(brs, 2H), 4.80(t,J=6Hz, 2H), 3.60(q, J=6Hz,2H), 2.87(t, J=7Hz, 2H), 2.0–1.8(m,17H),1.43(sextet, J=7Hz, 2H), 0.96(t, J=7Hz,3H) 119

(d₆-DMSO)δ 8.49(d, J=4.5Hz, 1H), 7.93(d, J=8Hz, 1H), 7.65(t, J=6Hz, 1H),7.45(dd, J=4.5, 8Hz, 1H), 7.29(d, J=8Hz, 2H),7.17(d, J=8Hz, 2H), 6.92(brs, 2H), 4.69(t,J=6Hz, 2H), 3.59(q, J=6Hz, 2H), 2.60(t,J=7Hz, 2H),2.28(m, 2H), 1.67(m, 4H),1.5–1.3(m, 6H), 0.92(t, J=7Hz, 3H) 120

(d₆-DMSO)δ 8.96(t, J=6Hz, 1H), 8.49(dd,J=4.0, 1.5, 1H), 7.92(dd, J=8,1.5Hz, 1H),7.50(d, J=8Hz, 2H), 7.44(dd, J=8, 4.0Hz,1H), 7.40(t, J=8Hz,1H), 6.76(s, 2H), 4.85(t, J=6Hz, 2H), 3.88(q, J=6Hz, 2H), 3.03(t,J=7Hz,2H), 1.80(quintet, J=7Hz, 2H),1.45(sextet, J=7Hz, 2H), 0.96(t, J=7Hz,3H)121

(d₆-DMSO)δ 8.52(dd, J=4.2, 1.5Hz, 1H),8.04(t, J=6Hz, 1H), 7.95(dd,J=8.5, 1.5Hz,1H), 7.45(dd, J=8.5, 4.2Hz, 1H), 7.4–7.2(m, 5H), 7.00(br s,2H), 4.84(t, J=6Hz,2H), 4.37(s, 2H), 3.74(s, 2H), 3.65(q, J=6Hz, 2H),2.87(t, J=7Hz, 2H), 1.77(quintet,J=7Hz, 2H), 1.40(sextet, J=7Hz, 2H),0.94(t, J=7Hz, 3H) 122

(d₆-DMSO)δ 8.50(dd, J=4.4, 1.5Hz, 1H),7.97(t, J=6Hz, 1H), 7.92(dd,J=8.4, 1.5Hz,1H), 7.45(dd, J=8.4, 1.5Hz, 1H), 6.75(br s,2H), 4.762(t,J=6Hz, 2H), 3.57(s, 3H), 2.88(t, J=7Hz, 2H), 2.27(t, J=7Hz, 4H),2.18(t,J=7Hz, 2H), 1.93(t, J=7Hz, 2H), 1.80(quintet, J=7Hz, 2H),2.6–1.1(m, 12H), 0.96(t, J=7Hz, 3H) 123

(d₆-DMSO)δ 8.52(dd, J=4.4, 1.5Hz, 1H),7.97(t, J=6Hz, 1H), 7.95(dd,J=8.3, 1.5Hz,1H), 7.45(dd, J=8.3, 4.4Hz, 1H), 6.88(br s,2H), 5.79(m,1H), 4.98(d, J=15Hz, 1H),4.91(d, J=13Hz, 1H), 4.76(t, J=6Hz, 2H),3.57(q,J=6Hz, 2H), 2.88(t, J=7Hz, 2H),2.00(q, J=7Hz, 2H), 1.93(t, J=6Hz,2H),1.80(quintet, J=7Hz, 2H), 1.44(sextet, J=7Hz, 2H), 1.5–1.1(m, 12H),0.96(t, J=6Hz,3H) 124

(d₆-DMSO)δ 8.51(dd, J=4.4, 1.7Hz, 1H),7.96(t, J=6Hz, 1H), 7.92(dd,J=8.3, 1.5Hz,1H), 7.44(dd, J=8.3, 4.4Hz, 1H), 6.81(br s,2H), 3.76(t,J=6Hz, 2H), 3.59(q, J=6Hz,2H), 2.90(t, J=7Hz, 2H), 1.94(m, 3H),1.80(quintet, J=7Hz, 2H), 1.58(m, 2H), 1.55–1.40(m, 6H), 0.96(m, 5H) 125

(d₆-DMSO)δ 9.32(t, J=6Hz, 1H), 8.51(dd,J=4.4, 1.5Hz, 1H), 8.29(br s,1H), 8.26(brs, 2H), 7.97(d, J=8Hz, 1H), 7.44(dd, J=8,4.4Hz, 1H), 7.42(brs, 2H), 4.97(t, J=6Hz,2H), 3.88(q, J=6Hz, 2H), 2.86(t, J=7Hz,2H),1.73(quintet, J=7Hz, 2H), 1.30(sextet,J=7Hz, 2H), 0.80(t, J=7Hz, 3H) 126

(d₆-DMSO)δ 8.68(d, J=4.5Hz, 1H), 8.61(t,J=6Hz, 1H), 8.12(d, J=8Hz, 1H),8.1(br s,2H), 7.62(dd, J=8.0, 4.5Hz, 1H), 7.44(dd,J=7.5, 2Hz, 1H),7.41(dt, J=7.5, 2.0Hz,1H), 7.31(dt, J=7.5, 2.0Hz, 1H), 7.12(dd,J=7.5,2Hz, 1H), 4.91(t, J=6Hz, 2H), 3.83(q, J=6Hz, 2H), 3.00(t, J=7Hz, 2H),1.83(quintet, J=7Hz, 2H), 1.44(sextet, J=7Hz,2H), 0.94(t, J=7Hz, 3H) 127

(d₆-DMSO)δ 8.69(t, J=6Hz, 1H), 8.63(dd,J=4, 1.5Hz, 1H), 8.07(d, J=8.5Hz,1H),7.80(br s, 2H), 7.65(d, J=2Hz, 1H), 7.57(dd, J=8.5, 4.5Hz, 1H),7.42(dd, J=8, 2Hz,1H), 7.15(d, J=8Hz, 1H), 4.91(t, J=6Hz,2H), 3.82(q,J=6Hz, 2H), 2.98(t, J=7Hz,2H), 1.82(quintet, J=7Hz, 2H),1.44(sextet,J=7Hz, 2H), 0.94(t, J=7Hz, 3H) 128

(d₆-DMSO)δ 8.48(dd, J=4.3, 1.5Hz, 1H),8.25(t, J=6Hz, 1H), 7.91(dd,J=8.5, 1.5Hz,1H), 7.42(dd, J=8.5, 4.3Hz, 1H), 7.25(t,J=8Hz, 1H), 6.74(brs, 2H), 6.61(d, J=8Hz, 2H), 4.80(t, J=6Hz, 2H), 3.76(q, J=6Hz, 2H),3.33(s, 6H), 3.00(t, J=7Hz, 2H),1.79(quintet, J=7Hz, 2H), 1.44(sextet,J=7Hz, 2H), 0.95(t, J=7Hz, 3H) 129

(d₆-DMSO)δ 8.66(t, J=6Hz, 1H), 8.57(dd,J=4.3, 1.2Hz, 1H), 8.00(dd,J=8.5, 1.2Hz,1H), 7.69(dd, J=9, 5.8Hz, 2H), 7.50(dd,J=8.4, 4.3Hz, 1H),7.30(br s, 2H), 7.25(t,J=9Hz, 2H), 4.91(t, J=6Hz, 2H), 3.81(q,J=6Hz,2H), 2.81(t, J=7Hz, 2H), 1.70(quintet, J=7Hz, 2H), 1.29(sextet,J=7Hz,2H), 0.81(t, J=7Hz, 3H) 130

(d₆-DMSO)δ 8.72(t, J=6Hz, 1H), 8.52(dd,J=4.3, 1.5Hz, 1H), 7.93(dd,J=8.0, 1.5Hz,1H), 7.72(d, J=8Hz, 2H), 7.50(d, J=8Hz,2H), 7.44(dd, J=8,4.3Hz, 1H), 6.80(br s,2H), 4.90(t, J=6Hz, 2H), 3.81(q, J=6Hz,2H),2.79(t, J=7Hz, 2H), 1.70(quintet, J=7Hz, 2H), 1.29(sextet, J=7Hz, 2H),0.81(t,J=7Hz, 3H) 131

(d₆-DMSO)δ 8.55(dd, J=4.3, 1.5Hz, 1H),8.49(t, J=6Hz, 1H), 7.95(dd,J=8.4, 1.5Hz,1H), 7.69(d, J=8Hz, 2H), 7.46(dd, J=8.4,4.3Hz, 1H), 6.93(d,J=8Hz, 2H), 6.91(br s,2H), 4.90(t, J=6Hz, 2H), 3.8(q, J≈6Hz,2H), 3.79(s,3H), 2.79(t, J=7Hz, 2H), 1.69(quintet, J=7Hz, 2H), 1.29(sextet,J=7Hz,2H), 0.80(t, J=7Hz, 3H) 132

(d₆-DMSO)δ 8.76(t, J=6Hz, 1H), 8.53(dd,J=4.3, 1.5Hz, 1H), 7.95(dd,J=8.5, 1.5Hz,1H), 7.67(br s, 1H), 7.65(d, J=8Hz, 1H),7.57(m, 1H),7.48–7.43(m, 2H), 7.02(br s,2H), 4.91(t, J=6Hz, 2H), 3.82(q, J=6Hz,2H),2.81(t, J=7Hz, 2H), 1.71(quintet, J=7Hz, 2H), 1.31(sextet, J=7Hz, 2H),0.82(t,J=7Hz, 3H) 133

(d₆-DMSO)δ 8.69(dd, J=4.4, 1.2Hz, 1H),8.57(t, J=6Hz, 1H), 8.22(br s,2H), 8.12(dd, J=8.0, 1.2Hz, 1H), 7.61(m, 3H), 7.41(d, J=9Hz, 2H),4.92(t, J=6Hz, 2H), 3.82(q, J=6Hz, 2H), 2.84(t, J=7Hz, 2H),1.68(quintet, J=7Hz, 2H), 1.27(sextet, J=7Hz,2H), 1.27(s, 9H), 0.78(t,J=7Hz, 3H) 134

(d₆-DMSO)δ 8.55(t, J=6Hz, 1H), 8.54(dd,J=4.5, 1.5Hz, 1H), 7.94(dd,J=8.5, 1.5Hz,1H), 7.60(d, J=8Hz, 2H), 7.46(dd, J=8.2,4.5Hz, 1H), 7.21(d,J=8Hz, 2H), 6.87(br s,2H), 4.90(t, J=6Hz, 2H), 3.80(q, J=6Hz,2H),2.80(t, J=7Hz, 2H), 2.32(s, 3H), 1.69(quintet J=7Hz, 2H), 1.29(sextet,J=7Hz,2H), 0.81(t, J=7Hz, 3H) 135

(d₆-DMSO)δ 8.58(dd, J=4.4, 1.5Hz, 1H),8.00(dd, J=8.4, 1.5Hz, 1H),7.97(t, J=6Hz,1H), 7.52(dd, J=8.4, 4.4Hz, 1H), 7.35(br s,2H), 4.77(t,J=6Hz, 2H), 3.58(q, J=6Hz,2H), 2.93(t, J=7Hz, 2H), 1.85(s, 2H),1.81(quintet, J=7Hz, 2H), 1.45(sextet, J=7Hz,2H), 0.96(t, J=7Hz, 3H),0.87(s, 9H) 136

(CDCl₃ at 60° C.)δ 8.56(dd, J=4.0, 1.5Hz,1H), 8.06(dd, J=8.5, 1.5Hz,1H), 7.41(dd,J=8.8, 4.0Hz, 1H), 6.80(br s, 1H), 5.70(brs, 2H), 4.94(t,J=6Hz, 2H), 3.82(q, J=6Hz,2H), 2.91(t, J=7Hz, 2H), 1.90(quintet, J=7Hz,2H), 1.51(sextet, J=7Hz, 2H), 0.99(m,1H), 0.99(t, J=7Hz, 3H), 0.79(m,2H), 0.54(m, 2H) 137

(CDCl₃)δ 8.59(dd, J=4.5, 1.5Hz, 1H), 8.10(dd, J=8.3, 1.5Hz, 1H),7.46(dd, J=8.5, 4.5Hz, 1H), 6.79(br s, 1H), 6.02(br s, 2H),4.96(t,J=6Hz, 2H), 3.82(q, J=6Hz, 2H),2.93(t, J=7Hz, 2H), 2.18(quintet,J=7Hz,1H), 1.90(quintet, J=7Hz, 2H), 1.65–1.35(m, 10H), 1.00(t, J=7Hz,3H) 138

(CDCl₃)δ 8.58(dd, J=4.4, 1.5Hz, 1H), 8.09(dd, J=8.0, 1.5Hz, 1H),7.46(dd, J=8.3, 4.4Hz, 1H), 7.00(br s, 1H), 5.85(br s, 2H),4.96(t,J=6Hz, 2H), 3.81(q, J=6Hz, 2H),2.92(t, J=7Hz, 2H), 1.88(m, 3H),1.52(m,6H), 1.50(m, 2H), 1.49(m, 2H), 1.291(q,2H), 1.01(t, J=7Hz, 3H),0.85(m, 2H) 139

(CDCl₃)δ 8.52(dd, J=4.4, 1.5Hz, 1H), 8.26(br t, 1H), 8.09(dd, J=8.5,1.5Hz, 1H), 7.47(d, J=8Hz, 2H), 7.46(dd, J=8.5, 4.4Hz,1H), 7.34(d,J=8Hz, 2H), 5.92(br s, 2H),5.12(t, J=6Hz, 2H), 4.04(q, J=6Hz,2H),2.93(t, J=7Hz, 2H), 1.92(quintet, J=7Hz,2H), 1.52(sextet, J=7Hz,2H), 1.00(t, J=7Hz, 3H) 140

(CDCl₃)δ 8.65(dd, J=4.4, 1.5Hz, 1H), 8.03(dd, J=8.5, 1.5Hz, 1H), 7.59(brt, 1H), 7.45(dd, J=8.5, 4.4Hz, 1H), 7.35(dd, J=5, 1.2Hz, 1H), 7.10(d,J=3Hz, 1H), 6.89(dd, J=5,3Hz, 1H), 6.32(br s, 2H), 5.08(t, J=6Hz,2H),4.02(q, J=6Hz, 2H), 2.92(t, J=7Hz,2H), 1.88(quintet, J=7Hz, 2H),1.47(sextet,J=7Hz, 2H), 0.96(t, J=7Hz, 3H) 141

(CDCl₃)δ 8.45(dd, J=4.4, 1.5Hz, 1H), 8.08(dd, J=8.4, 1.5Hz, 1H),7.43(dd, J=8.3, 4.4Hz, 1H), 7.07(dd, J=5, 1.6Hz, 1H), 6.84(brt, 1H),6.78(dd, J=5, 3.4Hz, 1H), 6.51(dd,J=3, 1Hz, 1H), 6.05(br s, 2H), 4.94(t,J=6Hz, 2H), 3.82(q, J=6Hz, 2H), 3.49(s, 2H),2.89(t, J=7Hz, 2H),1.88(quintet, J=7Hz,2H), 1.50(sextet, J=7Hz, 2H), 1.00(t, J=7Hz, 3H) 142

(CDCl₃)δ 8.52(dd, J=4.4, 1.5Hz, 1H), 8.42(br t, 1H), 8.08(dd, J=8.3,1.5Hz, 1H), 8.01(d, J=9Hz, 2H), 7.48(dd, J=8.4, 4.4Hz,1H), 7.39(d,J=9Hz, 2H), 5.80(br s, 2H),5.12(t, J=6Hz, 2H), 4.05(q, J=6Hz,2H),2.94(t, J=7Hz, 2H), 1.93(quintet, J=7Hz,2H), 1.52(sextet, J=7Hz,2H), 1.01(t, J=7Hz, 3H) 143

(CDCl₃)δ 8.21(dd, J=4.4, 1.5Hz, 1H), 8.05(dd, J=8.4, 1.5Hz, 1H), 7.53(brt, 1H), 7.28(dd, J=8.3, 4.4Hz, 1H), 6.68(s, 2H), 6.23(br s, 2H), 5.02(t,J=6Hz, 2H), 4.00(q, J=6Hz, 2H), 3.03(t, J=7Hz, 2H), 2.21(s, 3H),1.99(s,6H), 1.94(quintet, J=7Hz, 2H), 1.59(sextet, J=7Hz, 2H), 1.03(t, J=7Hz,3H) 144

(CDCl₃ at 29° C.)δ 8.59(dd, J=4.0, 1.5Hz,1H), 8.14(dd, J=8.0, 1.5Hz,1H), 8.09(dd,J=8, 1.5Hz, 1H), 7.87(t, J=6Hz, 1H), 7.42(t, J=8Hz, 1H),7.42(dd, J=8.0, 4.0Hz, 1H),7.06(t, J=8Hz, 1H), 6.87(d, J=8Hz,1H),6.19(br s, 2H), 5.07(t, J=6Hz, 2H), 4.04(q,J=6Hz, 2H), 3.68(s, 3H),2.89(t, J=7Hz,2H), 1.80(quintet, J=7Hz, 2H), 1.39(sextet,J=7Hz, 2H),0.88(t, J=7Hz, 3H) 145

(CDCl₃)δ 8.60(dd, J=4.4, 1.5Hz, 1H), 8.11(dd, J=8.5, 1.5Hz, 1H),7.47(dd, J=8.5, 4.4Hz, 1H), 7.01(br t, 1H), 6.43(br s, 2H), 4.95(t,J=6Hz, 2H), 3.81(q, J=6Hz, 2H), 3.63(s, 3H), 2.93(t, J=7Hz, 2H), 2.19(t,J=7Hz,2H), 1.92(m, 4H), 1.51(sextet, J=7Hz, 2H),1.42(m, 4H), 1.00(t,J=7Hz, 3H) 146

(CDCl₃)δ 8.23(dd, J=4.4, 1.5Hz, 1H), 8.52(br s, 1H), 8.10(dd, J=8.5,1.5Hz, 1H), 7.53(dd, J=8.3, 4.4Hz, 1H), 7.21(d, J=4Hz,1H), 7.06(d,J=4Hz, 1H), 6.1(br s, 2H),5.11(t, J=6Hz, 2H), 4.04(q, J=6Hz, 2H),2.94(t,J=7Hz, 2H), 1.93(quintet, J=7Hz,2H), 1.53(sextet, J=7Hz, 2H), 1.01(t,J=7Hz, 3H) 147

(CDCl₃)δ 8.39(dd, J=4.4, 1.5Hz, 1H), 8.31(dd, J=5.0, 2Hz, 1H), 8.21(brt, J=6Hz,1H), 8.00(dd, J=8.4, 1.5Hz, 1H), 7.42(dd,J=5, 8Hz, 1H),7.33(dd, J=8.5, 4.4Hz, 1H),7.07(dd, J=8, 5Hz, 1H), 5.84(br s,2H),5.06(t, J=6Hz, 2H), 4.05(q, J=6Hz, 2H),2.97(t, J=7Hz, 2H),1.93(quintet, J=7Hz,2H), 1.53(sextet, J=7Hz, 2H), 1.01(t, J=7Hz, 3H) 148

(CDCl₃ at 60° C.)δ 8.54(dd, J=4.4, 1.5Hz,1H), 8.33(d, J=2Hz, 1H),8.06(dd, J=8.4,1.5Hz, 1H), 8.06(br s, 1H), 7.56(dd, 8.5, 2Hz, 1H),7.45(dd, J=8.4, 4.4Hz, 1H), 7.15(d, J=8Hz, 1H), 5.72(br s, 2H), 5.08(t,J=6Hz, 2H), 4.03(q, J=6Hz, 2H), 2.93(t, J=7Hz, 2H), 1.93(quintet, J=7Hz,2H), 1.52(sextet, J=7Hz, 2H), 1.00(t, J=7Hz, 3H) 149

(CDCl₃)δ 8.61(dd, J=4.4, 1.5Hz, 1H), 8.03(dd, J=8.3, 1.5Hz, 1H), 7.50(t,J=6Hz, 1H),7.44(dd, J=8.3, 4.4Hz, 1H), 7.42(d, J=8Hz, 2H), 6.73(d,J=8Hz, 2H), 6.45(br s,2H), 5.06(t, J=6Hz, 2H), 4.00(q, J=6Hz,2H),3.90(t, J=7Hz, 2H), 2.90(t, J=7Hz,2H), 1.84(quintet, J=7Hz, 2H),1.74(quintet, J=7Hz, 2H), 1.42, m, 4H), 1.28(m,6H), 0.93(t, J=7Hz, 3H),0.87(t, 3H) 150

(CDCl₃)δ 8.61(dd, J=4.4, 1.5Hz, 1H), 8.09(d, J=8.5Hz, 1H), 7.90(d,J=8Hz, 2H), 7.84(br s, 1H), 7.48(dd, J=8.5, 4.4Hz, 1H), 7.44(d, J=8Hz,2H), 6.4(br s, 2H), 5.12(t, J=6Hz, 2H), 3.94(t, J=7Hz, 2H), 3.91(s,3H),2.94(t, J=7Hz, 2H), 1.91(quintet, J=7Hz,2H), 1.50(sextet, J=7Hz,2H), 0.99(t, J=7Hz, 3H) 151

(CDCl₃)δ 8.48(br s, 1H), 8.22(dd, J=4.5,1.5Hz, 1H), 8.04(dd, J=8.4,1.5Hz, 1H),7.33(s, 2H), 7.30(dd, J=8.4, 4.4Hz, 1H),5.96(br s, 2H),5.00(t, J=6Hz, 2H), 4.03(q,J=6Hz, 2H), 2.99(t, J=7Hz, 2H), 1.93(quintet,J=7Hz, 2H), 1.54(sextet, J=7Hz,2H), 1.03(t, J=7Hz, 3H) 152

(CDCl₃)δ 8.41(dd, J=4.4, 1.5Hz, 1H), 8.06(dd, J=8.3, 1.5Hz, 1H),7.41(dd, J=8.5, 4.4Hz, 1H), 6.75(d, J=8Hz, 2H), 6.64(d, J=8Hz, 2H),6.60(br t, 1H), 6.02(br s, 2H), 4.92(t, J=6Hz, 2H), 3.80(q, J=4.6Hz,2H), 3.76(s, 3H), 3.22(s, 2H), 2.88(t, J=7Hz, 2H),1.87(quintet, J=7Hz,2H), 1.50(sextet, J=7Hz, 2H), 1.00(t, J=7Hz, 3H)

EXAMPLES 153–190 Compounds of Formula I

The compounds of Examples 153–190 shown in the table below were preparedaccording to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(25 μmol) was dissolved in dichloromethane (10 mL) in a screw-cappedtest tube and the solution was cooled in an ice-water bath. An acidchloride (25 μmol) of the formula R_(A)COCl was added as a solution in100 μL of dichloromethane (Acid chlorides that are solids were addeddirectly.). The mixture was vortexed for 15 seconds to 1 minute,becoming cloudy, and then ˜80 mg of an aminomethyl polystyrene resin(0.62 meq/g, 100–200 mesh, 1% crosslink, Bachem #D-2100, lot # FM507)was added, and the mixture was vortexed for another 30 seconds. Themixture was applied to a short column (3×1 cm) of silica gel conditionedwith dichloromethane. The product was eluted with 10:1dichloromethane:methanol, collecting ˜2 mL fractions. Thin layerchromatography of the fractions was performed, and fractions with theproduct spot were pooled and stripped to dryness in a Savant SpeedVac.Purity was checked by reversed phase-HPLC (HPLC conditions refer tousing a Hewlett Packard HP 1090 system fitted with a C18 RaininMicrosorb MV column, 4.6×50 mm, particle size=3 microns, pore size=100Angstroms. Gradient elution: linear gradient from 100% water +0.1%trifluoroacetic acid to 100% acetonitrile +0.1% trifluoroacetic acidover 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm).APCI-mass spectral data confirmed presence of the expected molecularion, and proton nmr data supported the expected structure.

Example # R_(A) Fragment ¹H NMR(500MHz, solvent indicated) 153

(CDCl₃ at 29° C.)δ 8.53(dd, J=4.4, 1.5Hz,1H), 8.12(dd, J=8.5, 1.5Hz,1H), 7.83(t, J=2Hz, 1H), 7.59(d, J=8Hz, 1H), 7.57(d, J=8Hz, 1H),7.42(dd, J=8.5, 4.4Hz, 1H), 7.23(t,J=8Hz, 1H), 6.73(t, J=6Hz, 1H),6.50(br s,2H), 4.84(t, J=6Hz, 2H), 3.60(q, J=6Hz,2H), 2.92(t, J=7Hz,2H), 2.04(quintet, J=7Hz, 2H), 1.88(quintet, J=7Hz, 2H), 1.80(m,J=7Hz,2H), 1.48(m, 2H), 0.99(t, J=7Hz,3H) 154

(CDCl₃ at 29° C.)δ 8.60(dd, J=4.4, 1.5Hz,1H), 8.09(dd, J=8.5, 1.5Hz,1H), 7.43(dd,J=8.5, 4.4Hz, 1H), 6.32(br s, 2H), 5.75(t,J=6Hz, 1H),4.81(t, J=6Hz, 2H), 3.35(q,J=6Hz, 2H), 2.91(t, J=7Hz, 2H), 2.1–1.6(m,ca.21H), 1.51(sextet, J=7Hz, 2H), 1.01(t,J=7Hz, 3H) 155

(CDCl₃ at 60° C.)δ 8.44(dd, J=4.4, 1.5Hz,1H), 8.10(dd, J=8.5, 1.5Hz, 1H)7.43(dd,J=8.5, 4.4Hz, 1H), 7.10(s, 4H), 6.00(br s,2H), 5.60(t, J=6Hz,1H), 4.63(t, J=6Hz,2H), 3.30(q, J=6Hz, 2H), 2.86(t, J=7Hz,2H), 2.37(m,2H), 2.0–1.4(m, 14H), 1.01(t,J=7Hz, 3H) 156

(CDCl₃ at 60° C.)δ 8.33(d, J=4.4Hz, 1H),8.08(dd, J=8.5, 1.5Hz, 1H),7.5–7.0(m, 4H),6.70(br s, 1H), 6.25(br s, 2H), 4.85(t, J=6Hz, 2H),3.67(q, J=6Hz, 2H), 2.93(t, J=7Hz, 2H), 2.08(quintet, J=7Hz, 2H),1.89(m,4H), 1.53(sextet, J=7Hz, 2H), 1.02(t, J=7Hz, 3H) 157

(CDCl₃ at 60° C.)δ 8.59(dd, J=4.4, 1.5Hz,1H), 8.10(dd, J=8.5, 1.5Hz,1H), 7.40(dd,J=8.5, 4.4Hz, 1H), 7.28(m, 3H), 7.21(m,2H), 6.84(t, J=6Hz,1H), 6.4(br s, 2H), 4.81(t, J=6Hz, 2H), 4.49(s, 2H), 3.96(s, 2H),3.42(q,J=6Hz, 2H), 2.91(t, J=7Hz, 2H),1.95(quintet, J=7Hz, 2H), 1.90(quintet,J=7Hz, 2H), 1.69(quintet, J=7Hz, 2H), 1.51(sextet, J=7Hz, 2H), 1.01(t,J=7Hz, 3H) 158

(d₆-DMSO at 29° C.)δ 8.50(dd, J=4.4, 1.5Hz,1H), 7.91(dd, J=8, 1.5Hz,1H), 7.71(t, J=6Hz, 1H), 7.43(dd, J=8.4, 4.4Hz, 1H), 6.80(br s, 2H),4.79(t, J=6Hz, 2H), 3.57(s, 3H),3.05(q, J=6Hz, 2H), 2.28(q, J=7Hz,4H),2.20(t, J=7Hz, 2H), 1.98(t, J=7Hz, 2H),1.80(m, 4H), 1.6–1.1(m, 14H),0.96(t, J=7Hz, 3H) 159

(d₆-DMSO at 29° C.)δ 8.51(dd, J=4.4, 1.5Hz,1H), 7.92(dd, J=8.5, 4.4Hz,1H), 7.72(t, J=6Hz, 1H), 7.43(dd, J=8.5, 4.4Hz, 1H), 6.86(br s, 2H),5.77(m, 1H), 4.98(dd, J=2Hz,1H), 4.92(m, 1H), 4.79(t, J=6Hz, 2H),3.08(q, J=6Hz, 2H), 2.94(t, J=7Hz, 2H), 1.98(quintet, J=7Hz, 2H),1.80(m, 2H), 1.55–1.1(m, 20H), 0.96(t, J=7Hz, 3H) 160

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.4, 1.5Hz,1H), 7.90(dd, J=8.2, 1.5Hz,1H), 7.71(t, J=6Hz, 1H), 7.42(dd, J=8.2, 4.4Hz, 1H), 6.74(br s, 2H),4.79(t, J=6Hz, 2H), 3.06(q, J=6Hz, 2H), 2.92(t, J=7Hz, 2H), 2.04(m,1H),1.96(m, 2H), 1.82(m, 4H), 1.6–1.3(m, 10H),1.04(m, 2H), 0.96(t,J=7Hz, 3H) 161

(d₆-DMSO at 29° C.)δ 8.95(t, J=6Hz, 1H),8.44(m, 3H), 8.31(s, 1H),7.88(dd, J=8.5,1.5Hz, 1H), 7.37(dd, J=8.5, 4.4Hz, 1H),6.76(s, 2H),4.82(t, J=6Hz, 2H), 3.38(m,2H), 2.91(t, J=7Hz, 2H), 1.90(m, 2H), 1.76(m,2H), 1.64(m, 2H), 1.39(m, 2H), 0.86(t,J=7Hz, 3H) 162

(d₆-DMSO at 29° C.)δ 8.44(dd, J=4.4, 1.5Hz,1H), 8.39(t, J=6Hz, 1H),7.89(dd, J=8.2, 1.5Hz, 1H), 7.39(dd, J=8.2, 4.4Hz, 1H), 7.12(s, 2H),6.75(br s, 2H), 4.81(t, J=6Hz, 2H),3.78(s, 6H), 3.68(s, 3H), 3.32(m,2H), 2.92(m, 2H), 1.90(m, 2H), 1.80(m, 2H), 1.60(m,2H), 1.40(sextet,J=7Hz, 2H), 0.91(t, J=7Hz, 3H) 163

(d₆-DMSO at 29° C.)δ 8.89(t, J=6Hz, 1H),8.51(dd, J=4.4, 1.5Hz, 1H),7.93(d, J=8.5Hz, 1H), 7.44(dd, J=8.5, 4.4Hz, 1H), 6.95(br s, 2H),4.83(t, J=6Hz, 2H), 3.34(m, 2H),2.95(t, J=7Hz, 2H), 2.90(m, 2H),2.85(m,2H), 1.60(quintet, J=7Hz, 2H), 1.45(m, 2H),0.96(t, J=7Hz, 3H) 164

(d₆-DMSO at 29° C.)δ 8.50(dd, J=4.3, 1.5Hz,1H), 8.38(t, J=6Hz, 1H),7.91(dd, J=8.4, 1.5Hz, 1H), 7.44(dd, J=8, 1Hz, 1H), 7.39(dt,J=8, 1Hz,1H), 7.43(dd, J=8.4, 4.3Hz, 1H),7.31(dt(J=8, 1Hz, 1H), 7.27(dd, J=8,1Hz,1H), 6.74(s, 2H), 4.83(t, J=6Hz, 2H), 3.26(q, J=6Hz, 2H), 2.94(t,J=7Hz, 2H), 1.95(m, 2H), 1.83(m, 2H), 1.60(quintet, J=7Hz,2H), 1.45(m,2H), 0.95(t, J=7Hz, 3H) 165

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.3, 1.5Hz,1H), 8.44(t, J=6Hz, 1H),7.91(dd, J=8.2, 1.5Hz, 1H), 7.64(d, J=2Hz, 1H), 7.43(dd,J=8.2, 4.3Hz,1H), 7.42(dd, J=8, 2Hz, 1H),7.30(d, J=8Hz, 1H), 6.75(br s, 2H),4.82(t,J=6Hz, 2H), 3.25(q, J=6Hz, 2H), 2.93(t,J=7Hz, 2H), 1.90(m, 2H),1.82(m, 2H), 1.60(m, 2H), 1.45(sextet, J=7Hz, 2H), 0.95(t,J=7Hz, 3H) 166

(d₆-DMSO at 29° C.)δ 8.46(dd, J=4.3, 1.5Hz,1H), 8.46(m, 1H), 7.89(dd,J=8.5, 1.5Hz,1H), 7.84(dd, J=8, 5Hz, 2H), 7.40(dd,J=8.5, 4.3Hz, 1H),7.26(t, J=9Hz, 2H), 6.74(br s, 2H), 4.81(t, J=6Hz, 2H), 3.31(q, J=6Hz,2H), 2.91(t, J=7Hz, 2H), 1.88(m, 2H),1.79(m, 2H), 1.60(quintet, J=7Hz,2H), 1.45(m, 2H), 0.91(t, J=7Hz, 3H) 167

(d₆-DMSO at 29° C.)δ 8.53(t, J=6Hz, 1H),8.46(dd, J=4.4, 1.5Hz, 1H),7.89(dd, J=8.5,1.5Hz, 1H), 7.79(d, J=8Hz, 2H), 7.50(d,J=8.5Hz, 2H),7.40(dd, J=8.5, 4.3Hz, 1H),6.74(s, 2H), 4.81(t, J=6Hz, 2H),3.30(q,J=6Hz, 2H), 2.91(t, J=7Hz, 2H), 1.92(m,2H), 1.78(quintet, J=7Hz,2H), 1.60(quintet,J=7Hz, 2H), 1.40(sextet, J=7Hz, 2H), 0.90(t, J=7Hz,3H) 168

(d₆-DMSO at 29° C.)δ 8.47(dd, J=4.3, 1.5Hz,1H), 8.29(t, J=6Hz, 1H),7.89(dd, J=8.5, 1.5Hz, 1H), 7.76(d, J=8Hz, 2H), 7.40(dd,J=8.5, 4.3Hz,1H), 6.96(d, J=8Hz, 2H),6.74(s, 2H), 4.81(t, J=6Hz, 2H), 3.79(s,3H),3.39(q, J=6Hz, 2H), 2.91(t, J=7Hz,2H), 1.86(m, 2H), 1.79(quintet, J=7Hz,2H),1.60(quintet, J=7Hz, 2H), 1.41(sextet, J=7Hz, 2H), 0.91(t, J=7Hz,3H) 169

(d₆-DMSO at 29° C.)δ 8.67(t, J=6Hz, 1H),8.46(dd, J=4.0, 1.5Hz, 1H),7.97(d, J=8Hz,2H), 7.89(dd, J=8, 1.5Hz, 1H), 7.39(dd,J=8, 1.5Hz, 1H),7.38(d, J=8Hz, 2H), 6.74(s, 2H), 4.82(t, J=6Hz, 2H), 3.32(m, 2H),2.91(t,J=7Hz, 2H), 1.89(m, 2H), 1.78(quintet, J=7Hz, 2H), 1.62(quintet,J=7Hz,2H), 1.40(sextet, J=7Hz, 2H), 0.89(t, J=7Hz, 3H) 170

(d₆-DMSO at 29° C.)δ 8.46(dd, J=4.0, 1.5Hz,1H), 8.35(t, J=6Hz, 1H),7.89(dd, J=8.5, 1.5Hz, 1H), 7.71(d, J=8Hz, 2H), 7.43(d, J=8Hz, 2H),7.40(dd, J=8, 4.0Hz, 1H), 6.73(s,2H), 4.80(t, J=6Hz, 2H), 3.30(q,J=6Hz,2H), 2.91(t, J=7Hz, 2H), 1.88(quintet, J=7Hz, 2H), 2.80(quintet,J=7Hz, 2H), 1.60(m,2H), 1.39(sextet, J=7Hz, 2H), 1.29(s, 9H),0.90(t,J=7Hz, 3H) 171

(d₆-DMSO at 29° C.)δ 8.47(dd, J=4.0, 1.5Hz,1H), 8.35(t, J=6Hz, 1H),7.89(dd, J=8.0, 1.5Hz, 1H), 7.69(d, J=8Hz, 2H), 7.40(dd,J=8.0, 4.0Hz,1H), 7.23(d, J=8Hz, 2H),6.74(s, 2H), 4.81(t, J=6Hz, 2H), 3.28(q,J=6Hz,2H), 2.91(t, J=7Hz, 2H), 2.34(s,3H), 2.90(m, 2H), 1.79(quintet, J=7Hz,2H),1.60(quintet, J=7Hz, 2H), 1.41(sextet, J=7Hz, 2H), 0.91(t, J=7Hz,3H) 172

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.5, 1.5Hz,1H), 7.90(dd, J=8.5, 1.5Hz,1H), 7.67(t, J=6Hz, 1H), 7.42(dd, J=8.5, 4.5Hz, 1H), 6.74(s, 2H),4.79(t, J=6Hz, 2H), 3.06(q, J=6Hz,2H), 2.91(t, J=7Hz 2H), 1.87(s, 2H),1.82(quintet, J=7Hz, 4H), 1.46(sextet, J=7Hz,4H), 0.96(t, J=7Hz, 3H),0.86(s, 9H) 173

(d₆-DMSO at 29° C.)δ 8.50(dd, J=4.5, 1.5Hz,1H), 8.00(t, J=6Hz, 1H),7.90(dd, J=8.5, 1.5Hz, 1H), 7.43(dd, J=8.5, 4.5Hz, 1H), 6.75(s, 2H),4.79(t, J=6Hz, 2H), 3.10(q, J=6Hz,2H), 2.92(t, J=7Hz, 2H), 1.82(m, 4H),1.45(m, 5H), 0.94(t, J=7Hz, 3H), 0.60(m, 4H) 174

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.3, 1.5Hz,1H), 7.90(dd, J=8.4, 1.5Hz,1H), 7.68(t, J=6Hz, 1H), 7.42(dd, J=8.4, 4.3Hz, 1H), 6.73(br s, 2H),4.80(t, J=6Hz, 2H), 3.06(q, J=6Hz, 2H), 2.92(t, J=7Hz, 2H), 2.44(m,1H),1.81(m, 4H), 1.70–1.30(m, 12H), 0.96(t, J=7Hz, 3H) 175

(d₆-DMSO at 29° C.)δ 8.50(dd, J=4.5, 1.5Hz,1H), 7.90(dd, J=8.0, 1.5Hz,1H), 7.73(t, J=6Hz, 1H), 7.42(dd, J=8.0, 4.5Hz, 1H), 6.75(s, 2H),4.78(t, J=6Hz, 2H), 3.06(q, J=6Hz,2H), 2.92(t, J=7Hz, 2H), 1.99(t,J=7Hz,2H), 1.81(m, 4H), 1.63(m, 3H), 1.6–1.3(m,10H), 1.00(m, 2H),0.97(t, J=7Hz, 3H) 176

(d₆-DMSO at 29° C.)δ 8.69(t, J=6Hz, 1H),8.45(dd, J=4.3, 1.5Hz, 1H),7.91(m, 4H),7.89(dd, J=8.3, 1.5Hz, 1H), 7.40(dd, J=8.3,4.3Hz, 1H),6.74(s, 2H), 4.81(t, J=6Hz,2H), 3.31(m, 2H), 2.91(t, J=7Hz, 2H), 1.90(m,2H), 1.79(quintet, J=7Hz, 2H), 1.60(m,2H), 1.40(sextet, J=7Hz, 2H),0.90(t, J=7Hz, 3H) 177

(d₆-DMSO at 29° C.)δ 8.46(dd, J=4.3, 1.5Hz,1H), 8.45(t, J=6Hz, 1H),7.89(dd, J=8.4, 1.5Hz, 1H), 7.72(dd, J=5, 1Hz, 1H), 7.67(dd,J=3, 1Hz,1H), 7.40(dd, J=8.4, 4.3Hz, 1H),7.11(dd, J=5, 3Hz, 1H), 6.74(s, 2H),4.82(t,J=6Hz, 2H), 3.28(q, J=6Hz, 2H), 2.92(t,J=7Hz, 2H), 1.87(m, 2H),1.79(quintet, J=7Hz, 2H), 1.60(quintet, J=7Hz, 2H), 1.42(sextet, J=7Hz,2H), 0.91(t, J=7Hz, 3H) 178

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.3, 1.5Hz,1H), 8.05(t, J=6Hz, 1H),7.91(dd, J=8.2, 1.5Hz, 1H), 7.43(dd, J=8.2, 4.3Hz, 1H), 7.29(dd, J=5,1Hz, 1H), 6.89(dd, J=5, 3Hz, 1H),6.82(dd, J=3, 1Hz, 1H), 6.77(br s, 2H),4.79(t, J=6Hz, 2H), 3.56(s, 2H), 3.09(q, J=6Hz,2H), 2.90(t, J=7Hz, 2H),1.75(m, 4H), 1.45(m, 4H), 0.95(t, J=7Hz, 3H) 179

(d₆-DMSO at 29° C.)δ 8.77(t, J=6Hz, 1H),8.46(dd, J=4.4, 1.5Hz, 1H),8.28(dd, J=8.5,2.5Hz, 2H), 8.00(dd, J=8.5 2.5Hz, 2H),7.89(dd, J=8.3,1.5Hz, 1H), 7.39(dd, J=8.3,4.4Hz, 1H), 6.75(s, 2H), 4.82(t, J=6Hz,2H),3.32(m, 2H), 2.92(t, J=7Hz, 2H), 1.90(m, 2H), 1.79(quintet, J=7Hz, 2H),1.63(m,2H), 1.42(sextet, J=7Hz, 2H), 0.91(t, J=7Hz, 3H) 180

(d₆-DMSO at 29° C.)δ 8.48(dd, J=4.3, 1.5Hz,1H), 8.14(t, J=6Hz, 1H),7.91(dd, J=8.4, 1.5Hz, 1H), 7.42(dd, J=8.4, 4.3Hz, 1H), 6.78(s, 2H),6.75(br s, 2H), 4.82(t, J=6Hz, 2H),3.22(q, J=6Hz, 2H), 2.92(t, J=7Hz,2H),2.50(s, 3H), 2.03(s, 6H), 1.90(m, 2H), 1.85(quintet, J=7Hz, 2H),1.58(m, 2H), 1.45(sextet, J=7Hz, 2H), 0.96(t, J=7Hz, 3H) 181

(d₆-DMSO at 29° C.)δ 9.48(t, J=6Hz, 1H),8.52(d, J=4.3Hz, 1H), 7.94(d,J=8Hz, 1H),7.45(dd, J=8.0, 4.3Hz, 1H), 7.09(br s, 2H),4.80(t, J=6Hz,2H), 3.25(q, J=6Hz, 2H),2.92(t, J=7Hz, 2H), 1.81(m, 4H), 1.58(m,2H),1.45(sextet, J=7Hz, 2H), 0.95(t, J=7Hz, 3H) 182

(d₆-DMSO at 29° C.)δ 8.50(dd, J=4.3, 1.5Hz,1H), 7.90(dd, J=8.0, 1.5Hz,1H), 7.75(t, J=6Hz, 1H), 7.42(dd, J=8.0, 4.3Hz, 1H), 6.77(br s, 2H),4.78(t, J=6Hz, 2H), 3.56(s, 3H),3.06(q, J=6Hz, 2H), 2.90(t, J=7Hz,2H),2.25(m, 2H), 2.00(m, 2H), 1.81(m, 4H),1.44(m, 8H), 0.96(t. J=7Hz,3H) 183

(d₆-DMSO at 29° C.)δ 8.55(t, J=6Hz, 1H),8.50(dd, J=4.3, 1.5Hz, 1H),8.43(dd, J=5, 2Hz, 1H), 7.91(dd, J=8.4, 1.5Hz, 1H), 7.74(d, J=8.0, 2Hz,1H), 7.43(dd, J=8, 4.3Hz,1H), 7.42(dd, J=8, 5Hz, 1H), 6.75(br s,2H),4.83(t, J=6Hz, 2H), 3.27(q, J=6Hz, 2H),2.94(t, J=7Hz, 2H), 1.92(m,2H), 1.83(quintet, J=7Hz, 2H), 1.60(m, 2H), 1.46(sextet, J=7Hz, 2H),0.95(t, J=7Hz, 3H) 184

(d₆-DMSO at 29° C.)δ 8.77(dd, J=2.5, 0.5Hz,1H), 8.70(t, J=6Hz, 1H),8.46(dd, J=4.3, 1.5Hz, 1H), 8.16(dd, J=8, 3Hz, 1H), 7.91(dd,J=8.4,1.5Hz, 1H), 7.62(dd, J=8, 0.5Hz,1H), 7.43(dd, J=8.4, 1.5Hz, 1H), 6.76(brs,2H), 4.81(t, J=6Hz, 2H), 3.31(m, 2H), 2.92(t, J=7Hz, 2H), 1.89(m, 2H),1.79(quintet,J=7Hz, 2H), 1.61(quintet, J=7Hz, 2H), 1.40(sextet, J=7Hz,2H), 0.91(t, J=7Hz, 3H) 185

(d₆-DMSO at 29° C.)δ 8.55(t, J=6Hz, 1H),8.45(dd, J=4.3, 1.5Hz, 1H),7.90(d, J=8Hz,2H), 7.89(dd, J=8, 1.5Hz, 1H), 7.43(d, J=8Hz, 2H),7.39(dd, J=8, 4.3Hz, 1H), 6.74(brs, 2H), 4.81(t, J=6Hz, 2H), 3.30(m,2H),2.91(t, J=7Hz, 2H), 1.88(m, 2H), 1.78(quintet, J=7Hz, 2H), 1.63(m,2H), 1.34(sextet, J=7Hz, 2H), 0.89(t, J=7Hz, 3H) 186

(d₆-DMSO at 29° C.)δ 8.64(t, J=6Hz, 1H),8.49(dd, J=4.4, 1.5Hz, 1H),7.90(dd, J=8.5,1.5Hz, 1H), 7.69(s, 2H), 7.42(dd, J=8.5, 4.3Hz, 1H),6.74(s, 2H), 4.84(t, J=6Hz, 2H),3.26(q, J=6Hz, 2H), 2.93(t, J=7Hz,2H),1.90(m, 2H), 1.83(quintet, J=7Hz, 2H), 1.60(m, 2H), 1.46(sextet,J=7Hz, 2H), 0.96(t,J=7Hz, 3H) 187

(d₆-DMSO at 29° C.)δ 8.49(dd, J=4.3, 1.5Hz,1H), 7.92(t, J=6Hz, 1H),7.90(dd, J=8.5, 1.5Hz, 1H), 7.42(dd, J=8.5, 4.3Hz, 1H), 7.07(d, J=8Hz,2H), 6.76(d, J=8Hz, 2H), 6.74(br s, 2H), 4.79(t, J=6Hz, 2H), 3.70(s,3H),3.25(s, 2H), 3.08(q, J=6Hz, 2H), 2.89(t,J=7Hz, 2H), 1.80(m, 4H),1.46(m, 2H), 1.44(sextet, J=7Hz, 2H), 0.95(t, J=7Hz, 3H) 188

(d₆-DMSO at 29° C.)δ 8.47(dd, J=4.3, 1.5Hz,1H), 8.15(t, J=6Hz, 1H),7.90(dd, J=8.4, 1.5Hz, 1H), 7.64(dd, J=8, 2Hz, 1H), 7.41(dt,J=8, 2Hz,1H), 7.40(dd, J=8.4, 4.3Hz, 1H),7.06(d, J=8Hz, 1H), 6.98(dt, J=8,2Hz,1H), 6.74(s, 2H), 4.82(t, J=6Hz, 2H), 3.70(s, 3H), 3.33(m, 2H),2.92(t, J=7Hz, 2H),1.90(m, 2H), 1.80(quintet, J=7Hz, 2H), 1.60(m, 2H),1.43(sextet, J=7Hz, 2H), 0.92(t,J=7Hz, 3H) 189

(d₆-DMSO at 29° C.)δ 8.56(t, J=6Hz, 1H),8.46(dd, J=4.4, 1.5Hz, 1H),7.89(dd, J=8.4,1.5Hz, 1H), 7.82(t, J=2Hz, 1H), 7.74(td,J=8, 2Hz, 1H),7.58(td, J=8, 2Hz, 1H), 7.47(t, J=8Hz, 1H), 7.39(dd, J=8.4, 4.4Hz,1H),6.74(s, 2H), 4.81(t, J=6Hz, 2H), 3.31(q,J=6Hz, 2H), 2.91(t, J=7Hz,2H), 1.88(m,2H), 1.79(quintet, J=7Hz, 2H), 1.61(m, 2H),1.36(sextet,J=7Hz, 2H), 0.90(t, J=7Hz,3H) 190

(d₆-DMSO at 29° C.)δ 8.46(dd, J=4.3, 1.5Hz,1H), 8.27(t, J=6Hz, 1H),7.89(dd, J=8.5, 1.5Hz, 1H), 7.75(d, J=8Hz, 2H), 7.40(dd,J=8.5, 4.3Hz,1H), 6.94(d, J=8Hz, 2H),6.73(s, 2H), 4.81(t, J=6Hz, 2H), 4.00(t, J=7Hz,2H), 3.28(q, J=6Hz, 2H), 2.91(t, J=7Hz, 2H), 1.87(m, 2H), 1.78(quintet,J=7Hz,2H), 1.71(quintet, J=7Hz, 2H), 1.60(m, 2H),1.38(sextet, J=7Hz,4H), 1.32(m, 2H), 1.28(m, 4H), 0.91(t, J=7Hz, 3H), 0.87(t, J=7Hz,3H)

EXAMPLES 191–212 Compounds of Formula I

The compounds of Examples 191–212 shown in the table below were preparedaccording to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(50 μmol) was dissolved in 5 mL of dichloromethane in a screw-cappedtest tube and a carboxylic acid (50 μmol) of formula R_(A)COOH was addedat ambient temperature. Within 3 minutes a light suspension typicallyformed. The coupling agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (˜10.5 mg, 55 μmol) was added and the mixturewas vortexed at 400 rpm for 1–2 h at ambient temperature, giving a clearsolution in most cases. The mixture was applied to a short column (3×1cm) of silica gel conditioned with dichloromethane. The product waseluted with 10:1 dichloromethane:methanol, collecting ˜2 mL fractions.Thin layer chromatography of the fractions was performed, and fractionswith the product spot were pooled and stripped to dryness in a SavantSpeedVac. Purity was checked by reversed phase-HPLC (HPLC conditionsrefer to using a Hewlett Packard HP 1090 system fitted with a C18 RaininMicrosorb MV column, 4.6×50 mm, particle size=3 microns, pore size=100Angstroms. Gradient elution: linear gradient from 100% water +0.1%trifluoroacetic acid to 100% acetonitrile +0.1% trifluoroacetic acidover 5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm).APCI-mass spectral data confirmed presence of the expected molecularion, and proton nmr data supported the expected structure.

Example # R_(A) Fragment ¹H NMR(500MHz, solvent indicated) 191

(CDCl₃)δ 8.47(dd, J=4.4, 1.5Hz, 1H), 8.10(dd, J=8.5, 1.5Hz, 1H),7.45(dd, J=8.5, 4.4Hz, 1H), 7.15(dd, J=5.0, 3.0Hz, 1H), 6.75(d, J=3Hz,1H), 6.64(dd, J=5.0, 1.2Hz,1H), 6.61(br t, 1H), 6.3(br s, 2H),4.94(t,J=6Hz, 2H), 3.30(s, 2H), 2.81(q, J=6Hz,2H), 2.89(t, J=7Hz, 2H),1.88(quintet, J=7Hz, 2H), 1.50(sextet, J=7Hz, 2H), 1.00(t,J=7Hz, 3H) 192

(CDCl₃)δ 8.41(dd, J=4.4, 1.5Hz, 1H), 8.04(dd, J=8.5, 1.5Hz, 1H),7.40(dd, J=8.5, 4.4Hz, 1H), 7.34(dd, J=8, 1.2Hz, 1H), 7.07(dt,J=8, 2Hz,1H), 7.00(dt, J=8, 2Hz, 1H),6.96(dt, J=8, 2Hz, 1H), 6.78(br t, 1H),5.72(br s, 2H), 4.95(t, J=6Hz, 2H), 3.85(q, J=6Hz, 2H), 3.42(s, 2H),2.89(t, J=7Hz, 2H),1.83(quintet, J=7H, 2H), 1.50(sextet, J=7Hz, 2H),1.00(t, J=7Hz, 3H) 193

(CDCl₃)δ 8.40(dd, J=4.4, 1.5Hz, 1H), 8.07(dd, J=8.5, 1.5Hz, 1H),7.43(dd, J=8.5, 4.5Hz, 1H), 7.14(d, J=2Hz, 1H), 7.06(br t,1H), 6.98(dd,J=8, 2Hz, 1H), 6.85(d, J=8Hz, 1H), 5.75(br s, 2H), 4.96(t, J=6Hz,2H),3.86(q, J=6Hz, 2H), 3.31(s, 2H), 2.89(t, J=7Hz, 2H), 1.89(quintet,J=7Hz, 2H),1.50(sextet, J=7Hz, 2H), 1.00(t, J=7Hz,3H) 194

(CDCl₃)δ 8.59(dd, J=4.5, 1.8Hz, 1H), 8.09(dd, J=8.5, 1.8Hz, 1H),7.47(dd, J=8.5, 4.5Hz, 1H), 7.19(bt, 1H), 5.79(bs, 2H), 4.96(t,J=6Hz,2H), 3.82(q, J=6Hz, 2H), 3.36(t,J=6Hz, 2H), 2.92(t, J=7Hz, 2H),1.91(q,J=7Hz, 2H), 1.87(q, J=7Hz, 2H), 1.50(m,6H), 1.01(t, J=7Hz, 3H)195

(CDCl₃)δ 8.51(dd, J=4.5, 1.8Hz, 1H), 8.07(m, 3H), 7.42(dd, J=4.5, 8.5),1H), 7.31(brt, 1H), 7.14(d, J=8Hz, 2H), 5.8(s, 2H), 4.95(t, J=6Hz, 2H),4.257(t, J=7Hz, 2H), 3.80(q, J=6Hz, 2H), 2.94(t, J=7Hz, 2H),1.90(quintet, J=7Hz, 2H), 1.83(quintet, J=7Hz,2H), 1.50(sextet, J=7Hz,2H), 1.34(quintet,J=7Hz, 2H), 1.01(t, J=7Hz, 3H) 196

(CDCl₃)δ 8.60(dd, J=4.5, 1.5Hz, 1H), 8.11(dd, J=8.5, 1.5Hz, 1H),7.49(dd, J=8.5, 4.5Hz, 1H), 7.24(br s, 1H), 6.0(br s, 2H), 4.95(t,J=6Hz, 2H), 4.26(t, J=7Hz, 2H), 3.82(q,J=6Hz, 2H), 2.93(t, J=7Hz, 2H),1.91(quintet, J=7Hz, 2H), 1.83(m, 4H), 1.50(sextet, J=7Hz, 2H),1.35(quintet, J=7Hz,2H), 1.05(m, 2H), 1.01(t, J=7Hz, 3H) 197

(CDCl₃)δ 8.60(dd, J=4.5, 1.5, 1H), 8.11(dd, J=8.5, 1.5, 1H), 7.49(dd,J=8.5, 4.5Hz,1H), 7.01(d, J=8Hz, 2H), 6.76(d, J=8Hz,2H), 6.59(br s, 1H),5.69(br s, 2H), 4.93(t,J=6Hz, 2H), 3.80(q, J=6Hz, 2H), 3.20(s,2H),2.89(t, J=7Hz, 2H), 2.44(s, 3H), 1.90(quintet, J=7Hz, 2H), 1.51(sextet,J=7Hz,2H), 1.01(t, J=7Hz, 3H) 198

(CDCl₃)δ 8.58(dd, J=4.4, 1.5Hz, 1H), 8.09(dd, J=8.3, 1.5Hz, 1H),7.48(dd, J=8.3, 4.4Hz, 1H), 7.30(br t, 1H), 5.69(br s, 2H), 5.01(m, 3H),3.85(q, J=6Hz, 2H), 2.92(t, J=7Hz, 2H), 1.91(quintet, J=7Hz, 2H),1.85(m,1H), 1.79(m, 1H), 1.60(m, 2H), 1.52(sextet, J=7Hz, 2H), 1.38(d,J=9Hz, 1H),1.27(t, J=6Hz, 1H), 1.00(t, J=7Hz, 3H) 199

(CDCl₃)δ 8.59(dd, J=4.5, 1.5Hz, 1H), 8.11(dd, J=8.5, 1.5Hz, 1H),7.48(dd, J=8.5, 4.4Hz, 1H), 7.48(br s, 1H), 6.11(br s, 2H),4.94(t,J=6Hz, 2H), 3.83(q, J=6Hz, 2H),2.92(t, J=7Hz, 2H), 2.28(m, 2H),2.08(t,J=7Hz, 2H), 1.90(quintet, J=7Hz, 2H),1.52(sextet, J=7Hz, 2H),1.01(t, J=7Hz,3H) 200

(CDCl₃)δ 8.54(dd, J=4.4, 1.5Hz, 1H), 8.10(dd, J=8.4, 1.5Hz, 1H),7.46(dd, J=8.4, 4.4Hz, 1H), 7.19(br t, 1H), 7.12(d, J=8Hz,2H), 6.88(d,J=8Hz, 2H), 5.94(br s, 2H),4.91(t, J=6Hz, 2H), 3.78(q, J=6Hz,2H),2.90(t, J=7Hz, 2H), 2.65(t, J=7Hz, 2H),2.12(t, J=7Hz, 2H),1.86(quintet, J=7Hz,2H), 1.52(sextet, J=7Hz, 2H), 1.02(t, J=7Hz, 3H) 201

(CDCl₃)δ 8.60(dd, J=4.4, 1.5Hz, 1H), 8.12(dd, J=8, 1.5Hz, 1H), 7.47(dd,J=8.0, 4.4Hz, 1H), 6.86(br s, 1H), 6.20(br s, 2H),4.96(t, J=6Hz, 2H),3.81(q, J=6Hz, 2H),2.92(t, J=7Hz, 2H), 1.90(m, 4H), 1.51(sextet, J=7Hz,2H), 1.33(quintet, J=7Hz,2H), 1.23(m, 16H), 1.01(t, J=7Hz, 3H),0.87(t,J=7Hz, 3H) 202

(CDCl₃)δ 8.58(dd, J=4.3, 1.5Hz, 1H), 8.04(dd, J=8.0, 1.5Hz, 1H), 7.56(brs, 1H), 7.43(dd, J=8.0, 4.3Hz, 1H), 5.84(br s, 2H), 4.94(t, J=6Hz, 2H),4.89(br s, 1H), 3.85(q, J=6Hz, 2H), 3.54(d, J=6Hz, 2H), 2.92(t, J=7Hz,2H), 1.89(quintet, J=7Hz, 2H), 1.51(sextet, J=7Hz, 2H), 1.41(s, 9H),1.00(t,J=7Hz, 3H) 203

(CDCl₃)δ 8.60(d, J=4.4Hz, 1H), 8.07(dd,J=8.0, 1.5Hz, 1H), 7.59(br s,1H), 7.45(dd,J=8.5, 4.4Hz, 1H), 5.88(br s, 2H), 4.94(m,2H), 4.77(s, 1H),3.93(m, 1H), 3.84(m,2H), 2.94(t, J=7Hz, 2H), 1.89(quintet, J=7Hz, 2H),1.52(sextet, J=7Hz, 2H), 1.40(s,9H), 1.01(d, J=7Hz, 3H), 0.99(t,J=7Hz,3H) 204

(d₆-DMSO at 80° C.)δ 8.53(dd, J=4.4, 1.5Hz, 1H), 8.53(t, J=6Hz, 1H),7.96(dd,J=8.3, 1.5Hz, 1H), 7.45(dd, J=8.3, 4.4Hz,1H), 7.32(d, J=4Hz,1H), 7.16(d, J=4Hz,1H), 6.81(br s, 2H), 4.91(t, J=6Hz, 2H),3.78(q,J=6Hz, 2H), 2.85(t, J=7Hz, 2H),1.77(quintet, J=7Hz, 2H), 1.37(sextet,J=7Hz, 2H), 0.87(t, J=7Hz, 3H) 205

(CDCl₃)δ 9.16(d, J=1.4Hz, 1H), 8.66(dd,J=4.4, 1.5Hz, 1H), 8.44(t, J=6Hz,1H),8.11(d, J=1.4Hz, 1H), 8.09(dd, J=8.4, 1.5Hz, 1H), 7.47(dd, J=8.5,4.4Hz, 1H), 6.10(br s, 2H), 5.11(t, J=6Hz, 2H), 4.05(q, J=6Hz, 2H),2.92(t, J=7Hz, 2H), 2.59(s, 3H),1.87(quintet, J=7Hz, 2H), 1.46(sextet,J=7Hz, 2H), 0.95(t, J=7Hz, 3H) 206

(CDCl₃)δ 8.73(dd, J=4.4, 1.5Hz, 1H), 8.12(dd, J=8.4, 1.5Hz, 1H), 7.95(brs, 1H), 7.52(dd, J=8.4, 4.4Hz, 1H), 6.91(d, J=3.4Hz,1H), 6.31(d,J=3.4Hz, 1H), 6.04(br s, 2H),5.07(t, J=6Hz, 2H), 3.99(q, J=6Hz,2H),2.93(t, J=7Hz, 2H), 1.91(quintet, J=7Hz,2H), 1.50(sextet, J=7Hz,2H), 0.99(t, J=7Hz, 3H) 207

(CDCl₃)δ 8.50(dd, J=4.4, 1.5Hz, 1H), 8.42(d, J=4Hz, 1H), 8.19(d,J=1.5Hz, 1H), 8.09(dd, J=8.2, 1.5Hz, 1H), 7.47(dd, J=8.3, 4.4Hz, 1H),7.26(br s, 1H), 7.23(d, J=8Hz,1H), 7.07(dd, J=8.5, 5Hz, 1H), 6.06(brs,2H), 3.95(t, J=6Hz, 2H), 3.84(q, J=6Hz,2H), 3.21(s, 2H), 2.87(t,J=7Hz, 2H), 1.88(quintet, J=7Hz, 2H), 1.50(sextet, J=7Hz,2H), 1.00(t,J=7Hz, 3H) 208

(CDCl₃)δ 8.54(dd, J=4.4, 1.5Hz, 1H), 8.37(d, J=4Hz, 1H), 8.24(br s, 1H),8.09(dd,J=8.5, 1.5Hz, 1H), 7.46(dd, J=8.5, 4.4Hz,1H), 7.35(br t, 1H),7.27(td, J=8, 2Hz, 1H),7.08(dd, J=8, 5Hz, 1H), 5.98(br s, 2H),4.91(t,J=6Hz, 2H), 3.79(q, J=6Hz, 2H),2.90(t, J=7Hz, 2H), 2.69(t, J=7Hz,2H),2.14(t, J=7Hz, 2H), 1.90(quintet, J=7Hz,2H), 1.52(sextet, J=7Hz,2H), 1.01(t, J=7Hz, 3H) 209

(d₆-DMSO)δ 8.52(d, J=8.3Hz, 1H), 8.37(m, 2H), 7.96(d, J=8.3Hz, 1H),7.48(dd,J=8.3, 4.5Hz, 1H), 7.14(br s, 2H), 4.72(t,J=6Hz, 2H), 4.12(t,J=6Hz, 2H), 3.56(q,J=6Hz, 2H), 2.81(t, J=7Hz, 2H), 2.52(m,2H), 2.33(s,3H), 1.75(quintet, J=7Hz, 2H),1.40(sextet, J=7Hz, 2H), 0.94(t, J=7Hz,3H)210

(CDCl₃)δ 8.52(dd, J=4.4, 1.5Hz, 1H), 8.05(dd, J=8.4, 1.5Hz, 1H), 7.76(t,J=6Hz, 1H),7.43(dd, J=8.5, 4.4Hz, 1H), 7.27(d, J=8Hz, 2H), 7.06(d,J=8Hz, 2H), 5.82(br s,2H), 5.06&4.83(m, 2H), 3.88&3.79(m,2H), 3.03(m,1H), 2.89(t, J=7Hz, 2H), 2.79(m, 1H), 2.5(m, 3H), 2.25(m, 1H),1.90(quintet, J=7Hz, 2H), 1.51(sextet, J=7Hz,2H), 1.00(t, J=7Hz, 3H) 211

(d₆-DMSO)δ 8.53(dd, J=4.4, 1.5Hz, 1H),8.24(t, J=6Hz, 1H), 7.96(dd,J=8.4, 1.5Hz,1H), 7.84(m, 4H), 7.48(dd, J=4.4, 8.4Hz,1H), 7.18(br s,2H), 4.75(t, J=6Hz, 2H),3.73(t, J=7Hz, 2H), 3.52(q, J=6Hz, 2H),2.86(t,J=7Hz, 2H), 2.34(t, J=7Hz, 2H),1.79(quintet, J=7Hz, 2H), 1.40(sextet,J=7Hz, 2H), 0.92(t, J=7Hz, 3H) 212

(CDCl₃)δ 8.60(dd, J=4.4, 1.5Hz, 1H), 8.04(dd, J=8.5, 1.5Hz, 1H),7.68(dd, J=3.5, 1.2Hz, 1H), 7.61(dd, J=3.5, 1.2Hz, 1H), 7.43(dd, J=8.5,4.4Hz, 1H), 7.39(t, J=6Hz, 1H),7.10(dd, J=5, 3.5Hz, 1H), 5.79(br s,2H),4.93(t, J=6Hz, 2H), 3.82(q, J=6Hz, 2H),3.12(t, J=7Hz, 2H), 2.92(t,J=7Hz, 2H),2.32(t, J=7Hz, 2H), 1.89(quintet, J=7Hz,2H), 1.49(sextet,J=7Hz, 2H), 0.99(t, J=7Hz, 3H)

EXAMPLE 213 Compound of formula IIN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]5-oxo-2-pyrrolinecarboxamide

Using the general method of Example 97 L-pyroglutamic acid (0.23 g, 1.7mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmole) to provide 0.10 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxo-2-pyrrolinecarboxamideas a white powder, m.p. 135–138° C. Analysis: Calculated for C₂₀H₂₅N₇O₂½CH₃CN: % C, 60.63; % H, 6.42; % N, 25.25; Found: % C, 60.14; % H, 6.41;% N, 25.20. HRMS (EI) calcd for C₂₀H₂₅N₇O₂ (M+) 396.2103 found 396.2112.

Test Methods Cytokine Induction in Human Cells

An in vitro human blood cell system was used to assess cytokineinduction by compounds of the invention. Activity is based on themeasurement of interferon and tumor necrosis factor (ℑ) (IFN and TNF,respectively) secreted into culture media as described by Testerman et.al. In “Cytokine Induction by the Immunomodulators Imiquimod andS-27609”, Journal of Leukocyte Biology, 58, 365–372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood is collected by venipuncture into EDTA vacutainer tubes fromhealthy human donors. Peripheral blood mononuclear cells (PBMCs) areseparated from whole blood by Histopaque®-1077 (Sigma Chemicals, St.Louis, Mo.) density gradient centrifugation. The PBMCs are suspended at1.5–2×10⁶ cells/mL in RPMI 1640 medium containing 10% fetal bovineserum, 2 mM L-glutamine and 1% penicillin/streptomycin solution (RPMIcomplete). 1 mL portions of PBMC suspension are added to 24 well flatbottom sterile tissue culture plates.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested in aconcentration range of from 0.1 to 100 μM.

Incubation

The solution of test compound is added to the wells containing 1 mL ofPBMCs in media. The plates are covered with plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. with a 5% carbon dioxideatmosphere.

Separation

Following incubation the plates are centrifuged for 5–10 minutes at 1000rpm (˜200×g) at 4° C. The cell culture supernatant is removed with asterile polypropylene pipet and transferred to a 2 mL sterile cryotube.Samples are maintained at −70° C. until analysis.

Interferon Analysis/Calculation

Interferon is determined by bioassay using A549 human lung carcinomacells challenged with encephalomyocarditis. The details of the bioassaymethod have been described by G. L. Brennan and L. H. Kronenberg in“Automated Bioassay of Interferons in Micro-test Plates”, Biotechniques,June/Jul. 78, 1983, incorporated herein by reference. Briefly stated themethod is as follows: A549 cells are incubated with samples and standardinterferon dilutions at 37° C. for 24 hours. The incubated cells arethen infected with an inoculum of encephalomyocarditis virus. Theinfected cells are incubated for an additional 24 hours at 37° C. beforequantifying for viral cytopathic effect. The viral cytopathic effect isquantified by staining followed by visual scoring of the plates. Resultsare expressed as alpha reference units/mL based on the value obtainedfor NIH Human Leukocyte IFN standard.

Tumor Necrosis Factor (ℑ) Analysis

Tumor necrosis factor (ℑ) (TNF) concentration is determined using anELISA kit available from Genzyme, Cambridge, Mass. The results areexpressed as pg/mL.

In the table below, a “+” indicates that the compound induced theindicated cytokine at that particular concentration, a “−” indicatesthat the compound did not induce the indicated cytokine at thatparticular concentration, and a “±” indicates that the results wereequivocal at that particular concentration.

Cytokine Induction in Human Cells IFN TNF Dose Concentration (μM) DoseConcentration (μM) Example 0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 9 ± − +− − − − − 10 + + + + − − − + 12 Not run + + + Not run + + + 13 Notrun + + + Not run + + + 22 Not run − − − Not run − ± + 23 Not run + + −Not run − ± − 25 Not run − + + Not run − ± − 26 Not run + − + Not run +± − 27 Not run + + + Not run + + + 28 Not run + + + Not run − + + 32 Notrun + + + Not run − − − 33 Not run + + + Not run − − − 36 Not run + + +Not run − + − 39 Not run + + − Not run + + − 40 Not run + + ± Notrun + + + 45 + + + − − + + − 46 + + + + + + + + 46 Not run + + ± Notrun + + + 47 − + + ± − + + + 48 + + + − − + + − 49 + + + + − + + + 50Not run + + − Not run + + − 51 Not run + + + Not run + + − 52 Notrun + + − Not run + + − 53 + + + + − + + − 54 Not run + + + Notrun + + + 55 Not run + + + Not run + + − 56 − + + − − − + − 57 − + + + −− + + 58 + + + − − + + − 62 + + + + + + + + 65 + + + + − + + + 70 + + +− − + + − 75 − + + + − − + − 80 − + + − − − + − 85 + + + − − + + − 90± + + + − − + + 91 + + + + + + + + 92 ± + + + − + + + 93 − + + + − + + +94 − + + + − + + + 95 ± + + + − − + + 96 − ± + + − − + + 97 − − + + −− + + 98 − + + + − + + + 99 − − + + − − + + 100 − − + + − − + + 101 −− + + − − + + 101 − − + + − − − + 102 + + + + + + + + 103 − − + + −− + + 104 − + + − − − + − 105 + + + + − − + + 106 + + + − − + + −107 + + + − − + + − 108 + + + + ± − + + 109 + + + + − ± + + 110 + + + +− + + + 111 − − + + − − + + 112 + + + ± + + − − 113 − + + + − + + + 114− − + + − − + + 115 − − + + − − + + 116 − + + + − + + + 117 − − + + −− + + 118 Not run − + + Not run − + + 119 Not run − − − Not run − − −120 Not run + + + Not run − + + 121 Not run + + + Not run + + + 122 Notrun − + + Not run − + + 123 Not run ± − − Not run − ± − 124 Notrun + + + Not run − + + 125 Not run + + + Not run − + + 126 Notrun + + + Not run − + + 127 Not run + + + Not run − + + 128 Not run± + + Not run − ± + 129 Not run + + + Not run + + + 130 Not run + + +Not run + + + 131 Not run + + + Not run + + + 132 Not run + + + Notrun + + + 133 Not run + + + Not run + + + 134 Not run + + + Notrun + + + 135 Not run − + + Not run − + + 136 Not run + + + Not run− + + 137 Not run + + + Not run − ± + 138 Not run + + + Not run + + +139 Not run + + + Not run − + + 140 Not run + + + Not run + + + 141 Notrun + + + Not run − + + 142 Not run + + + Not run − + + 143 Not run− + + Not run − ± − 144 + + + + − + + + 145 − − + + − + + + 146 + + +− + + + + 147 − + + + − − + + 148 − + + + − − + + 149 − − − − − − − −150 − − + + − − + + 151 − − + + − − + + 152 − − + + − − + + 153 − + + −− + + − 155 − + + + − − + + 156 + + + + − + + − 157 + + + − − − + − 158− + + + − − + − 159 + + + − + + + + 160 + + + − − + + − 161 ± + + + −− + + 162 + + + + − + + + 163 + + + + − + + − 164 + + + − − + + −165 + + + + − + + + 166 − + + − − + + − 167 − + + − − − + − 168 − + + +− + + − 169 − + + + − − + + 170 − + + + − − + + 171 + + + ± − + + −172 + + + + − + + + 173 + + + + − + + + 174 + + + + + + + − 175 − + + −− + + − 176 − + + + − − + + 177 − − + − − − + − 178 + + + + + − + − 179− + + + − + + − 180 + + + + ± + + + 181 − − ± + − − − + 182 − + + +− + + − 183 − − − − − − − − 183 + + + − 184 + + + − + + + − 185 − + + ±− ± + − 186 + + + + − + + + 187 − + + + − + + − 188 + + + − − + + − 189− + + − − ± + − 190 + + + − − + + − 191 Not run + + + Not run − + + 192− − + + − − + + 193 − − + + − − + + 194 − + + + − + + + 195 − − + −− + + + 196 − − + + − − + + 197 − − + + − + + + 198 − − + + − + + +199 + − + + − − + + 200 − − + + − − + + 201 − − − − − − − + 202 − − + +− − + + 203 − − + + − − + + 204 + + + + − + + + 205 + + + + − + + +206 + + + + − + + + 207 − − + + − − + + 208 − − + + − − − − 208 − ± + +209 − − + + − − + + 210 − − + + + + + + 211 − − + + − − + + 212 − + + +− + + +

Interferon (α) Induction in Human Cells

An in vitro human blood cell system was used to assess interferoninduction by compounds of the invention. Activity is based on themeasurement of interferon secreted into culture media. Interferon ismeasured by bioassay.

Blood Cell Preparation for Culture

Whole blood was collected by venipuncture into EDTA vacutainer tubes.Peripheral blood mononuclear cells (PBM's) were separated from wholeblood by using either LeucoPREP™ Brand Cell Separation Tubes (availablefrom Becton Dickinson) or Ficoll-Paque® solution (available fromPharmacia LKB Biotechnology Inc, Piscataway, N.J.). The PBM's weresuspended at 1×10⁶/mL in RPMI 1640 media (available from GIBCO, GrandIsland, N.Y.) containing 25 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid) and L-glutamine(1% penicillin-streptomycin solution added) with 10% heat inactivated(56° C. for 30 minutes) autologous serum added. 200 μL portions of PBMsuspension were added to 96 well (flat bottom) Micro Test III steriletissue culture plates.

Compound Preparation

The compounds were solubilized in ethanol, dimethyl sulfoxide or tissueculture water then diluted with tissue culture water, 0.01N sodiumhydroxide or 0.01N hydrochloric acid (The choice of solvent will dependon the chemical characteristics of the compound being tested.). Ethanolor DMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells. Compounds were initially tested in aconcentration range of from about 0.1 μg/mL to about 5 μg/mL. Compoundswhich show induction at a concentration of 0.5 μg/mL were then tested ina wider concentration range.

Incubation

The solution of test compound was added in a volume (less than or equalto 50 μL) to the wells containing 200 μL of diluted whole blood or ofPBM's in media. Solvent and/or media was added to control wells (wellswith no test compound) and as needed to adjust the final volume of eachwell to 250 μL. The plates were covered with plastic lids, vortexedgently and then incubated for 48 hours at 37° C. with a 5% carbondioxide atmosphere.

Separation

Following incubation, the plates were covered with parafilm and thencentrifuged at 1000 rpm for 10 to 15 minutes at 4° C. in a Damon IECModel CRU-5000 centrifuge. Media (about 200 μL) was removed from 4 to 8wells and pooled into 2 mL sterile freezing vials. Samples weremaintained at −70° C. until analysis.

Interferon Analysis/Calculation

Interferon was determined by bioassay using A549 human lung carcinomacells challenged with encephalomyocarditis. The details of the bioassaymethod have been described by G. L. Brennan and L. H. Kronenberg in“Automated Bioassay of Interferons in Micro-test Plates”, Biotechniques,June/Jul. 78, 1983, incorporated herein by reference. Briefly stated themethod is as follows: interferon dilutions and A549 cells are incubatedat 37° C. for 12 to 24 hours. The incubated cells are infected with aninoculum of encephalomyocarditis virus. The infected cells are incubatedfor an additional period at 37° C. before quantifying for viralcytopathic effect. The viral cytopathic effect is quantified by stainingfollowed by spectrophotometric absorbance measurements. Results areexpressed as alpha reference units/mL based on the value obtained forNIH HU IF-L standard. The interferon was identified as essentially allinterferon alpha by testing in checkerboard neutralization assaysagainst rabbit anti-human interferon (beta) and goat anti-humaninterferon (alpha) using A549 cell monolayers challenged withencephalomyocarditis virus.

In the table below, a “+” indicates that the compound induced interferonα at that particular concentration, a “−” indicates that the compounddid not induce interferon α at that particular concentration, and a “±”indicates that the results were equivocal at that particularconcentration.

Interferon (α) Induction in Human Cells Ex- am- Dose Concentration(μg/mL) ple 0.01 0.05 0.10 0.50 1.0 5.0 10.0 25.0 50.0  9 − − − − − − −− − 10 − − − − + + + + + 12 − − + + + + + + + 13 − + + + + + + + + 22not not not run not run − − − + not run run run 23 not not not run notrun − − − − not run run run 25 − − − − − + + + not run 26 − − − − −± + + not run 27 − − + + + + + + not run 28 − ± + + + + + + not run 32 −− − − + + + + + 33 − − − − − + + + + 36 − + + + + + + + + 39 −− + + + + + + + 40 − + + + + + + + +

The present invention has been described with reference to severalembodiments thereof. The foregoing detailed description and exampleshave been provided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention should not be limited to theexact details of the compositions and structures described herein, butrather by the language of the claims that follow.

1. A compound of formula

wherein A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;R₇ is OH, halogen, or NHR₁, R₁ is selected from the group consisting of:-hydrogen; —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: -aryl; -heteroaryl; -heterocyclyl; —O—C₁₋₂₀ alkyl,—O—(C₁₋₂₀ alkyl)₀₋₁-aryl; —O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; —C₁₋₂₀ alkoxycarbonyl; —S(O)₀₋₂—C₁₋₂₀ alkyl;—S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; —S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;—S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; —N(R₃)₂; —N₃; oxo; -halogen;—NO₂; —OH; and —SH; and —C₁₋₂₀ alkyl-NR₃—Q—X—R₄ or —C₂₋₂₀alkenyl-NR₃—Q—X—R₄ wherein Q is —CO— or —SO₂—; X is a bond, —O— or —NR₃—and R₄ is aryl; heteroaryl; heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀alkenyl that is unsubstituted or substituted by one or more substituentsselected from the group consisting of: -aryl; -heteroaryl;-heterocyclyl; —O—C₁₋₂₀ alkyl, —O—(C₁₋₂₀ alkyl)₀₋₁-aryl; —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl; —O—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; —C₁₋₂₀alkoxycarbonyl; —S(O)₀₋₂—C₁₋₂₀ alkyl; —S(O)₀₋₂—C₁₋₂₀ alkyl)₀₋₁-aryl;—S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; —N(R₃)₂; —NR₃—CO—O—C₁₋₂₀alkyl; —N₃; oxo;-halogen; —NO₂; —OH; and —SH; or R₄ is

wherein Y is —N— or —CR—; R₈ is H, NO₂ or NH₂; each R₃ is independentlyselected from the group consisting of hydrogen and C₁₋₁₀ alkyl; and eachR is independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.